bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–01–28
sixty-nine papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury.
  2. GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity to Aspergillus fumigatus.
  3. Insights into the role of the respiratory tract microbiome in defense against bacterial pneumonia.
  4. Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.
  5. A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism.
  6. Dupilumab Alters Both the Bacterial and Fungal Skin Microbiomes of Patients with Atopic Dermatitis.
  7. Microbe Interactions within the Skin Microbiome.
  8. The cooperation between orf virus and Staphylococcus aureus leads to intractable lesions in skin infection.
  9. Heparin-binding hemagglutinin of Mycobacterium tuberculosis inhibits autophagy via TLR4 and drives M2 polarization in macrophages.
  10. Antigen presenting cells in cancer immunity and mediation of immune checkpoint blockade.
  11. Epitranscriptional m6A modification of rRNA negatively impacts translation and host colonization in Staphylococcus aureus.
  12. Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.
  13. A Functional Assessment of Fetal Liver and Monocyte-Derived Macrophages in the Lung Alveolar Environment.
  14. Cutting Edge: Cytosolic Receptor AIM2 Is Induced by Peroxisome Proliferator-activated Receptor γ following Mycobacterium tuberculosis Infection of Human Macrophages but Does Not Contribute to IL-1β Release.
  15. The cutaneous microbiome in skin cancer - A systematic review.
  16. Eliminating the invading extracellular and intracellular FnBp+ bacteria from respiratory epithelial cells by autophagy mediated through FnBp-Fn-Integrin α5β1 axis.
  17. Methodological Considerations in Longitudinal Analyses of Microbiome Data: A Comprehensive Review.
  18. Editorial: Pathogenic and symbiotic bacteria in ruminants: antimicrobial resistance and microbial homeostasis.
  19. Intraepithelial Lymphocytes of the Intestine.
  20. Respiratory tract barrier dysfunction in viral-bacterial co-infection cases.
  21. The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.
  22. Deciphering agr quorum sensing in Staphylococcus aureus: insights and therapeutic prospects.
  23. Rhinovirus protease cleavage of nucleoporins: perspective on implications for airway remodeling.
  24. Composition and interaction of maternal microbiota with immune mediators during pregnancy and their outcome: A narrative review.
  25. Association between periodontitis and inflammatory comorbidities: The common role of innate immune cells, underlying mechanisms and therapeutic targets.
  26. Utilization of a Histoplasma capsulatum zinc reporter reveals the complexities of fungal sensing of metal deprivation.
  27. JAK1 hits a nerve.
  28. Macrophage plasticity and function in cancer and pregnancy.
  29. Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis.
  30. Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.
  31. Recreating Human Skin In Vitro: Should the Microbiota Be Taken into Account?
  32. Integrating airway microbiome and blood proteomics data to identify multi-omic networks associated with response to pulmonary infection.
  33. Lactobacillus johnsonii LJO02 (DSM 33828) Cell-Free Supernatant and Vitamin D Improve Wound Healing and Reduce Interleukin-6 Production in Staphylococcus aureus-Infected Human Keratinocytes.
  34. Exploring the Complexity of the Interaction between T. rubrum and S. aureus/S. epidermidis in the Formation of Polymicrobial Biofilms.
  35. An In Vitro Model to Assess Early Immune Markers Following Co-Exposure of Epithelial Cells to Carbon Black (Nano)Particles in the Presence of S. aureus: A Role for Stressed Cells in Toxicological Testing.
  36. Surfactant protein D prevents mucin overproduction in airway goblet cells via SIRPα.
  37. Mechanisms and Potential Clinical Implications of Oral Microbiome in Oral Squamous Cell Carcinoma.
  38. SGK1 aggravates idiopathic pulmonary fibrosis by triggering H3k27ac-mediated macrophage reprogramming and disturbing immune homeostasis.
  39. NF-κB RelA is a cell-intrinsic metabolic checkpoint restricting glycolysis.
  40. Stably-Inverted Apical-Out Human Upper Airway Organoids for SARS-CoV-2 Infection and Therapeutic Testing.
  41. Time-lapse mesoscopy of Candida albicans and Staphylococcus aureus dual-species biofilms reveals a structural role for the hyphae of C. albicans in biofilm formation.
  42. Highly-resolved within-species dynamics in the human facial skin microbiome.
  43. Mucosal boosting.
  44. A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues.
  45. The role of the Notch signaling pathway in bacterial infectious diseases.
  46. Variation in the basal immune state and implications for disease.
  47. In vitro antibacterial activity of antiretroviral drugs on key commensal bacteria from the human microbiota.
  48. Editorial: Glycans: molecules at the interface of immunity and disease.
  49. Lactobacillus rhamnosus dampens cytokine and chemokine secretion from primary human nasal epithelial cells infected with rhinovirus.
  50. Therapeutic Effects of IL-1RA against Acute Bacterial Infections, including Antibiotic-Resistant Strains.
  51. Pharmacological Improvement of CFTR Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.
  52. Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.
  53. Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients.
  54. Inflammaging and fatty acid oxidation in monocytes and macrophages.
  55. Cell death proteins in sepsis: key players and modern therapeutic approaches.
  56. Advances and Applications of Lung Organoids in the Research on Acute Respiratory Distress Syndrome (ARDS).
  57. A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.
  58. Leveraging Microbiome Composition Variability for Precision Medicine in Idiopathic Pulmonary Fibrosis.
  59. MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections.
  60. Possible modulating functions of probiotic Lactiplantibacillus plantarum in particulate matter-associated pulmonary inflammation.
  61. Microbiome in Cancer Development and Treatment.
  62. Macrophage Polarization and Osteoclast Differentiation.
  63. Streptococcal arginine deiminase system defences macrophage bactericidal effect mediated by XRE family protein XtrSs.
  64. Probiotics in milk replacer affect the microbiome of the lung in neonatal dairy calves.
  65. Lactobacillus rhamnosus ameliorates acne vulgaris in SD rats via changes in gut microbiota and associated tryptophan metabolism.
  66. Macrophage barrier in the tumor microenvironment and potential clinical applications.
  67. The Skin Microbiome and its Significance for Dermatologists.
  68. From Birth to Weaning: A Window of Opportunity for Microbiota.
  69. Biofilm Producing Methicillin-Resistant Staphylococcus aureus (MRSA) Infections in Humans: Clinical Implications and Management.
  1. Adv Sci (Weinh). 2024 Jan 26. e2308978
    Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury.
    Yoon-Young Kang, Dong-Young Kim, Sang-Yong Lee, Hee-Joong Kim, Taehawn Kim, Jeong A Cho, Taewon Lee, Eun Young Choi.
      Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders.
    Keywords:  alveolar macrophages; efferocytosis; inflammation; lung injury; trained immunity
    DOI:  https://doi.org/10.1002/advs.202308978
  2. bioRxiv. 2024 Jan 04. pii: 2024.01.03.574062. [Epub ahead of print]
    GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity to Aspergillus fumigatus.
    Kathleen A M Mills, Frederike Westermann, Vanessa Espinosa, Eric Rosiek, Jigar V Desai, Mariano A Aufiero, Yahui Guo, Kennedy A Mitchell, Selma Tuzlak, Donatella De Feo, Michail S Lionakis, Amariliz Rivera, Burkhard Becher, Tobias M Hohl.
      Aspergillus fumigatus causes life-threatening mold pneumonia in immune compromised patients, particularly in those with quantitative or qualitative defects in neutrophils. While innate immune cell crosstalk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced IL-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF-responsive neutrophils, with the latter being essential for host survival. Our findings establish SPC + epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens.
    HIGHLIGHTS: GM-CSF is essential for host defense against A. fumigatus in the lung IL-1 and IFN-λ promote GM-CSF production by lung epithelial cells in parallelEpithelial cell-derived GM-CSF increases neutrophil accumulation and fungal killing capacityEpithelial cells preferentially upregulate GM-CSF in local sites of inflammation.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2024.01.03.574062
  3. Curr Opin Microbiol. 2024 Jan 25. pii: S1369-5274(24)00004-3. [Epub ahead of print]77 102428
    Insights into the role of the respiratory tract microbiome in defense against bacterial pneumonia.
    Zoe G Drigot, Sarah E Clark.
      The respiratory tract microbiome (RTM) is a microbial ecosystem inhabiting different niches throughout the airway. A critical role for the RTM in dictating lung infection outcomes is underlined by recent efforts to identify community members benefiting respiratory tract health. Obligate anaerobes common in the oropharynx and lung such as Prevotella and Veillonella are associated with improved pneumonia outcomes and activate several immune defense pathways in the lower airway. Colonizers of the nasal cavity, including Corynebacterium and Dolosigranulum, directly impact the growth and virulence of lung pathogens, aligning with robust clinical correlations between their upper airway abundance and reduced respiratory tract infection risk. Here, we highlight recent work identifying respiratory tract bacteria that promote airway health and resilience against disease, with a focus on lung infections and the underlying mechanisms driving RTM-protective benefits.
    DOI:  https://doi.org/10.1016/j.mib.2024.102428
  4. Cells. 2024 Jan 16. pii: 166. [Epub ahead of print]13(2):
    Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.
    Abdullah A Tarique, Neeraj Tuladhar, Dean Kelk, Nelufa Begum, Richard M Lucas, Lin Luo, Jennifer L Stow, Claire E Wainwright, Scott C Bell, Peter D Sly, Emmanuelle Fantino.
       BACKGROUND: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF.
    METHODS: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed.
    RESULTS: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected; however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM d'd not restore endocytosis in CF, another essential feature of M2 macrophages.
    CONCLUSIONS: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.
    Keywords:  CFTR; ERK1/2; Pseudomonas aeruginosa; antibiotic resistance; azithromycin; bacterial killing; cystic fibrosis; macrophage polarization; phagocytosis
    DOI:  https://doi.org/10.3390/cells13020166
  5. Front Immunol. 2023 ;14 1334205
    A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism.
    Mehakpreet K Thind, Holm H Uhlig, Michael Glogauer, Nades Palaniyar, Celine Bourdon, Agnes Gwela, Christina L Lancioni, James A Berkley, Robert H J Bandsma, Amber Farooqui.
      Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries.
    Keywords:  autophagy; glycolysis; immune mediated diseases; metabolic reprogramming; mitochondrial respiration; neutrophil differentiation
    DOI:  https://doi.org/10.3389/fimmu.2023.1334205
  6. Microorganisms. 2024 Jan 22. pii: 224. [Epub ahead of print]12(1):
    Dupilumab Alters Both the Bacterial and Fungal Skin Microbiomes of Patients with Atopic Dermatitis.
    Naoka Umemoto, Maki Kakurai, Takanao Matsumoto, Kenta Mizuno, Otomi Cho, Takashi Sugita, Toshio Demitsu.
      The skin microbiome at lesion sites in patients with atopic dermatitis (AD) is characterized by dysbiosis. Although the administration of dupilumab, an IL-4Rα inhibitor, improves dysbiosis in the bacterial microbiome, information regarding the fungal microbiome remains limited. This study administered dupilumab to 30 patients with moderate-to-severe AD and analyzed changes in both fungal and bacterial skin microbiomes over a 12-week period. Malassezia restricta and M. globosa dominated the fungal microbiome, whereas non-Malassezia yeast species increased in abundance, leading to greater microbial diversity. A qPCR analysis revealed a decrease in Malassezia colonization following administration, with a higher reduction rate observed where the pretreatment degree of colonization was higher. A correlation was found between the group classified by the Eczema Area and Severity Index, the group categorized by the concentration of Thymus and activation-regulated chemokine, and the degree of skin colonization by Malassezia. Furthermore, an analysis of the bacterial microbiome also confirmed a decrease in the degree of skin colonization by the exacerbating factor Staphylococcus aureus and an increase in the microbial diversity of the bacterial microbiome. Our study is the first to show that dupilumab changes the community structure of the bacterial microbiome and affects the fungal microbiome in patients with AD.
    Keywords:  Malassezia; Staphylococcus aureus; atopic dermatitis; dupilumab; dysbiosis; skin microbiome
    DOI:  https://doi.org/10.3390/microorganisms12010224
  7. Antibiotics (Basel). 2024 Jan 04. pii: 49. [Epub ahead of print]13(1):
    Microbe Interactions within the Skin Microbiome.
    Thaís Glatthardt, Rayssa Durães Lima, Raquel Monteiro de Mattos, Rosana Barreto Rocha Ferreira.
      The skin is the largest human organ and is responsible for many important functions, such as temperature regulation, water transport, and protection from external insults. It is colonized by several microorganisms that interact with each other and with the host, shaping the microbial structure and community dynamics. Through these interactions, the skin microbiota can inhibit pathogens through several mechanisms such as the production of bacteriocins, proteases, phenol soluble modulins (PSMs), and fermentation. Furthermore, these commensals can produce molecules with antivirulence activity, reducing the potential of these pathogens to adhere to and invade human tissues. Microorganisms of the skin microbiota are also able to sense molecules from the environment and shape their behavior in response to these signals through the modulation of gene expression. Additionally, microbiota-derived compounds can affect pathogen gene expression, including the expression of virulence determinants. Although most studies related to microbial interactions in the skin have been directed towards elucidating competition mechanisms, microorganisms can also use the products of other species to their benefit. In this review, we will discuss several mechanisms through which microorganisms interact in the skin and the biotechnological applications of products originating from the skin microbiota that have already been reported in the literature.
    Keywords:  Cutibacterium acnes; Staphylococcus; microbial signaling; quorum sensing; skin microbiota
    DOI:  https://doi.org/10.3390/antibiotics13010049
  8. Front Cell Infect Microbiol. 2023 ;13 1213694
    The cooperation between orf virus and Staphylococcus aureus leads to intractable lesions in skin infection.
    Yongzhong Yu, Yudong Cui, Baifen Song.
      A large amount of evidence shows that different kinds of microorganisms can jointly cope with environmental pressures including cell hosts. For example, in many cases, it has been found that secondary or mixed infection of animals caused by ORFV (an epitheliophilic Parapoxvirus) and bacteria (such as Staphylococcus aureus or Streptococcus) shows a mutual aid mode that indirectly leads to the deterioration of the disease. However, the lack of research on the co-pathogenic mechanism, including how to hijack and destroy the cell host in the pathological microenvironment, has hindered the in-depth understanding of the pathogenic process and consequences of this complex infection and the development of clinical treatment methods. Here, we summarized the current strategies of trapping cell hosts together, based on the previously defined ORFV-Host (O-H) system. The opportunistic invasion of S. aureus destroyed the delicate dynamic balance of the O-H, thus aggravating tissue damage through bacterial products (mediated by Agr), even causing sepsis or inducing cytokine storms. In fact, the virus products from its adaptive regulatory system (VARS) weaken the immune attacks and block molecular pathways, so that S. aureus can settle there more smoothly, and the toxins can penetrate into local tissues more quickly. This paper focuses on the main challenges faced by cell hosts in dealing with mixed infection, which provides a starting point for us to deal with this disease in the future.
    Keywords:  Orf virus; Staphylococcus aureus; damage superposition; pathologic mechanism; secondary infections
    DOI:  https://doi.org/10.3389/fcimb.2023.1213694
  9. J Infect Dis. 2024 Jan 24. pii: jiae030. [Epub ahead of print]
    Heparin-binding hemagglutinin of Mycobacterium tuberculosis inhibits autophagy via TLR4 and drives M2 polarization in macrophages.
    Qing Zheng, Zhi Li, Yu Zhou, Yuru Li, Meiliang Gong, Heqiang Sun, Xinli Deng, Yueyun Ma.
       BACKGROUND: Tuberculosis (TB), predominantly caused by Mycobacterium tuberculosis (MTB) infection, remains a prominent global health challenge. Macrophages are the frontline defense against MTB, relying on autophagy for intracellular bacterial clearance. However, MTB can combat and evade autophagy, and it influences macrophage polarization, facilitating immune evasion and promoting infection. We previously found that heparin-binding hemagglutinin (HBHA) inhibits autophagy in A549 cells; however, its role in macrophage autophagy and polarization remains unclear.
    METHODS: Bacterial cultures, cell cultures, western blotting, immunofluorescence, macrophage infection assays, siRNA knockdown, and ELISA were used to investigate HBHA's impact on macrophages and its relevance in Mycobacterium infection.
    RESULTS: HBHA inhibited macrophage autophagy. Expression of recombinant HBHA in Mycobacterium smegmatis (rMS-HBHA) inhibited autophagy, promoting bacterial survival within macrophages. Conversely, HBHA knockout in the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) mutant (BCG-ΔHBHA) activated autophagy and reduced bacterial survival. Mechanistic investigations revealed that HBHA may inhibit macrophage autophagy through the TLR4-dependent PI3K-AKT-mTOR signaling pathway. Furthermore, HBHA induced macrophage M2 polarization.
    CONCLUSIONS: Mycobacterium may exploit HBHA to suppress the antimicrobial immune response in macrophages, facilitating intracellular survival, and immune evasion through autophagy inhibition and M2 polarization induction. Our findings may help identify novel therapeutic targets and develop more effective treatments against MTB infection.
    Keywords:  HBHA; TLR4; autophagy; macrophage; polarization
    DOI:  https://doi.org/10.1093/infdis/jiae030
  10. Clin Exp Metastasis. 2024 Jan 23.
    Antigen presenting cells in cancer immunity and mediation of immune checkpoint blockade.
    Cassia Wang, Lee Chen, Doris Fu, Wendi Liu, Anusha Puri, Manolis Kellis, Jiekun Yang.
      Antigen-presenting cells (APCs) are pivotal mediators of immune responses. Their role has increasingly been spotlighted in the realm of cancer immunology, particularly as our understanding of immunotherapy continues to evolve and improve. There is growing evidence that these cells play a non-trivial role in cancer immunity and have roles dependent on surface markers, growth factors, transcription factors, and their surrounding environment. The main dendritic cell (DC) subsets found in cancer are conventional DCs (cDC1 and cDC2), monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), and mature and regulatory DCs (mregDC). The notable subsets of monocytes and macrophages include classical and non-classical monocytes, macrophages, which demonstrate a continuum from a pro-inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype, and tumor-associated macrophages (TAMs). Despite their classification in the same cell type, each subset may take on an immune-activating or immunosuppressive phenotype, shaped by factors in the tumor microenvironment (TME). In this review, we introduce the role of DCs, monocytes, and macrophages and recent studies investigating them in the cancer immunity context. Additionally, we review how certain characteristics such as abundance, surface markers, and indirect or direct signaling pathways of DCs and macrophages may influence tumor response to immune checkpoint blockade (ICB) therapy. We also highlight existing knowledge gaps regarding the precise contributions of different myeloid cell subsets in influencing the response to ICB therapy. These findings provide a summary of our current understanding of myeloid cells in mediating cancer immunity and ICB and offer insight into alternative or combination therapies that may enhance the success of ICB in cancers.
    Keywords:  Antigen presenting cells; Cancer immunity; Dendritic cell; Immune checkpoint blockade; Macrophage; Monocyte
    DOI:  https://doi.org/10.1007/s10585-023-10257-z
  11. PLoS Pathog. 2024 Jan 22. 20(1): e1011968
    Epitranscriptional m6A modification of rRNA negatively impacts translation and host colonization in Staphylococcus aureus.
    Kathryn E Shields, David Ranava, Yongjun Tan, Dapeng Zhang, Mee-Ngan F Yap.
      Macrolides, lincosamides, and streptogramin B (MLS) are structurally distinct molecules that are among the safest antibiotics for prophylactic use and for the treatment of bacterial infections. The family of erythromycin resistance methyltransferases (Erm) invariantly install either one or two methyl groups onto the N6,6-adenosine of 2058 nucleotide (m6A2058) of the bacterial 23S rRNA, leading to bacterial cross-resistance to all MLS antibiotics. Despite extensive structural studies on the mechanism of Erm-mediated MLS resistance, how the m6A epitranscriptomic mark affects ribosome function and bacterial physiology is not well understood. Here, we show that Staphylococcus aureus cells harboring m6A2058 ribosomes are outcompeted by cells carrying unmodified ribosomes during infections and are severely impaired in colonization in the absence of an unmodified counterpart. The competitive advantage of m6A2058 ribosomes is manifested only upon antibiotic challenge. Using ribosome profiling (Ribo-Seq) and a dual-fluorescence reporter to measure ribosome occupancy and translational fidelity, we found that specific genes involved in host interactions, metabolism, and information processing are disproportionally deregulated in mRNA translation. This dysregulation is linked to a substantial reduction in translational capacity and fidelity in m6A2058 ribosomes. These findings point to a general "inefficient translation" mechanism of trade-offs associated with multidrug-resistant ribosomes.
    DOI:  https://doi.org/10.1371/journal.ppat.1011968
  12. Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2314627121
    Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.
    Xaria X Li, Jenny N Fung, Richard J Clark, John D Lee, Trent M Woodruff.
      The complement factor C5a is a core effector product of complement activation. C5a, acting through its receptors C5aR1 and C5aR2, exerts pleiotropic immunomodulatory functions in myeloid cells, which is vital for host defense against pathogens. Pattern-recognition receptors (PRRs) are similarly expressed by immune cells as detectors of pathogen-associated molecular patterns. Although there is evidence of cross talk between complement and PRR signaling pathways, knowledge of the full potential for C5a-PRR interaction is limited. In this study, we comprehensively investigated how C5a signaling through C5a receptors can modulate diverse PRR-mediated cytokine responses in human primary monocyte-derived macrophages and observed a powerful, concentration-dependent bidirectional effect of C5a on PRR activities. Unexpectedly, C5a synergized with Dectin-1, Mincle, and STING in macrophages to a much greater extent than TLRs. Notably, we also identified that selective Dectin-1 activation using depleted zymosan triggered macrophages to generate cell-intrinsic C5a, which acted on intracellular and cell surface C5aR1, to help sustain mitochondrial ROS generation, up-regulate TNFα production, and enhance fungal killing. This study adds further evidence to the holistic functions of C5a as a central immunomodulator and important orchestrator of pathogen sensing and killing by phagocytes.
    Keywords:  C5a; Dectin-1; complement; cytokine; macrophage
    DOI:  https://doi.org/10.1073/pnas.2314627121
  13. J Immunol. 2024 Jan 22. pii: ji2300626. [Epub ahead of print]
    A Functional Assessment of Fetal Liver and Monocyte-Derived Macrophages in the Lung Alveolar Environment.
    Wen Xuan Zhang, Arpan Sharma Neupane, Bruna Araujo David, Florent Ginhoux, Fernanda Vargas E Silva Castanheira, Paul Kubes.
      It is becoming clear that every organ is seeded by a population of fetal liver-derived macrophages that are replaced at different rates by monocyte-derived macrophages. Using the Ms4a3tdTomato reporter mouse that reports on monocyte-derived alveolar macrophages (Mo-AMs) and our ability to examine AM function using our multichannel intravital microscopy, we examined the fetal-liver derived alveolar macrophage (FL-AM) and Mo-AM populations within the same mouse under various environmental conditions. The experiments unveiled that AMs migrated from alveolus to alveolus and phagocytosed bacteria identically regardless of ontogenic origin. Using 50 PFU of influenza A virus (IAV) determined using the Madin-Darby canine kidney (MDCK) cell line, we noted that both populations were susceptible to IAV-induced immunoparalysis, which also led to impaired phagocytosis of secondary bacterial infections. Both FL-AMs and Mo-AMs were trained by β-glucan to resist IAV-induced paralysis. Over time (40 wk), Mo-AMs began to outperform FL-AMs, although both populations were still sensitive to IAV. Our data also show that clodronate depletion of AMs leads to replenishment, but by FL-AMs, and these macrophages do show some functional impairment for a limited time. Overall, the system is designed such that new macrophages rapidly assume the function of tissue-resident macrophages when both populations are examined in an identical environment. These data do differ from artificial depletion methods that compare Mo-AMs and FL-AMs.
    DOI:  https://doi.org/10.4049/jimmunol.2300626
  14. J Immunol. 2024 Jan 22. pii: ji2300418. [Epub ahead of print]
    Cutting Edge: Cytosolic Receptor AIM2 Is Induced by Peroxisome Proliferator-activated Receptor γ following Mycobacterium tuberculosis Infection of Human Macrophages but Does Not Contribute to IL-1β Release.
    Eusondia Arnett, Jade Wolff, Chrissy M Leopold Wager, Jan Simper, Jeanine L Badrak, Carlos O Ontiveros, Bin Ni, Larry S Schlesinger.
      AIM2 (absent in melanoma 2), an inflammasome component, mediates IL-1β release in murine macrophages and cell lines. AIM2 and IL-1β contribute to murine control of Mycobacterium tuberculosis (M.tb) infection, but AIM2's impact in human macrophages, the primary niche for M.tb, remains unclear. We show that M.tb, Mycobacterium bovis bacillus Calmette-Guérin (BCG), and M. smegmatis induce AIM2 expression in primary human macrophages. M.tb-induced AIM2 expression is peroxisome proliferator-activated receptor γ (PPARγ)-dependent and M.tb ESX-1-independent, whereas BCG- and M. smegmatis-induced AIM2 expression is PPARγ-independent. PPARγ and NLRP3, but not AIM2, are important for IL-1β release in response to M.tb, and NLRP3 colocalizes with M.tb. This is in contrast to the role for AIM2 in inflammasome activation in mice and peritoneal macrophages. Altogether, we show that mycobacteria induce AIM2 expression in primary human macrophages, but AIM2 does not contribute to IL-1β release during M.tb infection, providing further evidence that AIM2 expression and function are regulated in a cell- and/or species-specific manner.
    DOI:  https://doi.org/10.4049/jimmunol.2300418
  15. J Dtsch Dermatol Ges. 2024 Jan 20.
    The cutaneous microbiome in skin cancer - A systematic review.
    Ruojun Ding, ShengYang Bertrand Lian, Yew Chong Tam, Choon Chiat Oh.
      The overall incidence of skin cancer has risen over the past half a decade worldwide and is associated with significant morbidity and mortality. Recent advances in molecular testing have allowed us to better characterize microbiome alterations in skin cancer. However, literature specific to skin microbiome and skin cancer remain heterogenous and scattered. A systematic review was performed to identify the existing literature and its usefulness in providing microbiome-based biomarkers. A search of the databases (PubMed, Medline, EMBASE, GoogleScholar) was conducted from June to July 2022 in accordance with the PRISMA guidelines. A total of 1,543 articles were identified, of which 16 were selected for inclusion in the review (11 articles on cancer of the keratinocytes and 5 articles on melanoma). Increased Staphylococcus (S.) aureus prevalence with decline in commensal organisms is seen in squamous cell carcinoma (SCC) and actinic keratosis (AK), compared to healthy skin. While the microbiome of melanoma appears to be distinct from healthy skin, limited data is available to draw meaningful conclusions. Our review summarizes the current evidence on the microbiome of keratinocyte skin cancers and melanoma. The study establishes that the microbiome of these cancers is altered from healthy skin and that this dysbiosis involves both pathogenic and commensal organisms.
    DOI:  https://doi.org/10.1111/ddg.15294
  16. Front Cell Infect Microbiol. 2023 ;13 1324727
    Eliminating the invading extracellular and intracellular FnBp+ bacteria from respiratory epithelial cells by autophagy mediated through FnBp-Fn-Integrin α5β1 axis.
    Meiqi Meng, Jiachao Wang, Hongru Li, Jiao Wang, Xuan Wang, Miao Li, Xue Gao, Wenjian Li, Cuiqing Ma, Lin Wei.
       Background: We previously found that the respiratory epithelial cells could eliminate the invaded group A streptococcus (GAS) through autophagy induced by binding a fibronectin (Fn) binding protein (FnBp) expressed on the surface of GAS to plasma protein Fn and its receptor integrin α5β1 of epithelial cells. Is autophagy initiated by FnBp+ bacteria via FnBp-Fn-Integrin α5β1 axis a common event in respiratory epithelial cells?
    Methods: We chose Staphylococcus aureus (S. aureus/S. a) and Listeria monocytogenes (L. monocytogenes/L. m) as representatives of extracellular and intracellular FnBp+ bacteria, respectively. The FnBp of them was purified and the protein function was confirmed by western blot, viable bacteria count, confocal and pull-down. The key molecule downstream of the action axis was detected by IP, mass spectrometry and bio-informatics analysis.
    Results: We found that different FnBp from both S. aureus and L. monocytogenes could initiate autophagy through FnBp-Fn-integrin α5β1 axis and this could be considered a universal event, by which host tries to remove invading bacteria from epithelial cells. Importantly, we firstly reported that S100A8, as a key molecule downstream of integrin β1 chain, is highly expressed upon activation of integrin α5β1, which in turn up-regulates autophagy.
    Conclusions: Various FnBp from FnBp+ bacteria have the ability to initiate autophagy via FnBp-Fn-Integrin α5β1 axis to promote the removal of invading bacteria from epithelial cells in the presence of fewer invaders. S100A8 is a key molecule downstream of Integrin α5β1 in this autophagy pathway.
    Keywords:  FnBp; FnBp+ bacteria; Integrin α5β1; S100A8; autophagy
    DOI:  https://doi.org/10.3389/fcimb.2023.1324727
  17. Genes (Basel). 2023 Dec 28. pii: 51. [Epub ahead of print]15(1):
    Methodological Considerations in Longitudinal Analyses of Microbiome Data: A Comprehensive Review.
    Ruiqi Lyu, Yixiang Qu, Kimon Divaris, Di Wu.
      Biological processes underlying health and disease are inherently dynamic and are best understood when characterized in a time-informed manner. In this comprehensive review, we discuss challenges inherent in time-series microbiome data analyses and compare available approaches and methods to overcome them. Appropriate handling of longitudinal microbiome data can shed light on important roles, functions, patterns, and potential interactions between large numbers of microbial taxa or genes in the context of health, disease, or interventions. We present a comprehensive review and comparison of existing microbiome time-series analysis methods, for both preprocessing and downstream analyses, including differential analysis, clustering, network inference, and trait classification. We posit that the careful selection and appropriate utilization of computational tools for longitudinal microbiome analyses can help advance our understanding of the dynamic host-microbiome relationships that underlie health-maintaining homeostases, progressions to disease-promoting dysbioses, as well as phases of physiologic development like those encountered in childhood.
    Keywords:  deep learning; longitudinal analysis; microbiome data; review; statistical methods
    DOI:  https://doi.org/10.3390/genes15010051
  18. Front Vet Sci. 2023 ;10 1355704
    Editorial: Pathogenic and symbiotic bacteria in ruminants: antimicrobial resistance and microbial homeostasis.
    Yi Yang, Jilei Zhang, Heba Sayed El-Mahallawy.
      
    Keywords:  antimicrobial resistance; dysbiosis; microbial homeostasis; microbiome; pathogenic bacteria; ruminant; symbiotic bacteria
    DOI:  https://doi.org/10.3389/fvets.2023.1355704
  19. Annu Rev Immunol. 2024 Jan 26.
    Intraepithelial Lymphocytes of the Intestine.
    Ainsley Lockhart, Daniel Mucida, Angelina M Bilate.
      The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-immunol-090222-100246
  20. Jpn Dent Sci Rev. 2024 Dec;60 44-52
    Respiratory tract barrier dysfunction in viral-bacterial co-infection cases.
    Tomoko Sumitomo, Shigetada Kawabata.
      A preceding viral infection of the respiratory tract predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality. However, the underlying mechanism of the viral-bacterial synergy that leads to disease progression has remained elusive, thus hampering the production of effective prophylactic and therapeutic intervention options. In addition to viral-induced airway epithelial damage, which allows dissemination of bacteria to the lower respiratory tract and increases their invasiveness, dysfunction of immune defense following a viral infection has been implicated as a factor for enhanced susceptibility to secondary bacterial infections. Given the proximity of the oral cavity to the respiratory tract, where viruses enter and replicate, it is also well-established that oral health status can significantly influence the initiation, progression, and pathology of respiratory viral infections. This review was conducted to focus on the dysfunction of the respiratory barrier, which plays a crucial role in providing physical and secretory barriers as well as immune defense in the context of viral-bacterial synergy. Greater understanding of barrier response to viral-bacterial co-infections, will ultimately lead to development of effective, broad-spectrum therapeutic approaches for prevention of enhanced susceptibility to these pathogens.
    Keywords:  Co-infection; Influenza virus; Oral bacteria; Pneumonia; Streptococcus pneumoniae
    DOI:  https://doi.org/10.1016/j.jdsr.2023.12.006
  21. Front Immunol. 2023 ;14 1344697
    The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.
    Yina An, Shuyu Tan, Jingjing Yang, Ting Gao, Yanjun Dong.
      Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization.
    Keywords:  Hippo; inflammatory diseases; macrophage polarization; metabolism; regulatory network
    DOI:  https://doi.org/10.3389/fimmu.2023.1344697
  22. Mol Biol Rep. 2024 Jan 22. 51(1): 155
    Deciphering agr quorum sensing in Staphylococcus aureus: insights and therapeutic prospects.
    V Vinodhini, M Kavitha.
      The emergence of superbugs like methicillin-resistant Staphylococcus aureus exposed the limitations of treating microbial infections using antibiotics. At present, the discovery of novel and convincing therapeutic methods are being executed increasingly as possible substitutes to conventional antibiotic therapies. The quorum sensing helps Staphylococcus aureus become more viable through their signaling mechanisms. In recent years, targeting the prominent factors of quorum sensing has obtained remarkable attention as a futuristic approach to dealing with bacterial pathogenicity. The standard antibiotic therapy intends to inhibit the organism by targeting specific molecules and afford a chance for the evolution of antibiotic resistance. This prompts the development of novel therapeutic strategies like inhibiting quorum sensing that can limit bacterial virulence by decreasing the selective pressure, thereby restricting antibiotic resistance evolution. This review furnishes new insights into the accessory gene regulator quorum sensing in Staphylococcus aureus and its inhibition by targeting the genes that regulate the operon. Further, this review comprehensively explores the inhibitors reported up to date and their specific targets and discusses their potentially ineffective alternative therapy against methicillin-resistant Staphylococcus aureus.
    Keywords:  AIP signal molecule; Agr quorum sensing; Quorum sensing; Quorum sensing inhibition; Staphylococcus aureus
    DOI:  https://doi.org/10.1007/s11033-023-08930-3
  23. Front Microbiol. 2023 ;14 1321531
    Rhinovirus protease cleavage of nucleoporins: perspective on implications for airway remodeling.
    Jennifer Moorhouse, Nicole Val, Shadi Shahriari, Michelle Nelson, Regan Ashby, Reena Ghildyal.
      Human Rhinoviruses (RV) are a major cause of common colds and infections in early childhood and can lead to subsequent development of asthma via an as yet unknown mechanism. Asthma is a chronic inflammatory pulmonary disease characterized by significant airway remodeling. A key component of airway remodeling is the transdifferentiation of airway epithelial and fibroblast cells into cells with a more contractile phenotype. Interestingly, transforming growth factor-beta (TGF-β), a well characterized inducer of transdifferentiation, is significantly higher in airways of asthmatics compared to non-asthmatics. RV infection induces TGF-β signaling, at the same time nucleoporins (Nups), including Nup153, are cleaved by RV proteases disrupting nucleocytoplasmic transport. As Nup153 regulates nuclear export of SMAD2, a key intermediate in the TGF-β transdifferentiation pathway, its loss of function would result in nuclear retention of SMAD2 and dysregulated TGF-β signaling. We hypothesize that RV infection leads to increased nuclear SMAD2, resulting in sustained TGF-β induced gene expression, priming the airway for subsequent development of asthma. Our hypothesis brings together disparate studies on RV, asthma and Nup153 with the aim to prompt new research into the role of RV infection in development of asthma.
    Keywords:  airway remodeling; asthma; nucleoporin (Nup) 153; rhinovirus; transdifferentiation
    DOI:  https://doi.org/10.3389/fmicb.2023.1321531
  24. Life Sci. 2024 Jan 24. pii: S0024-3205(24)00029-8. [Epub ahead of print] 122440
    Composition and interaction of maternal microbiota with immune mediators during pregnancy and their outcome: A narrative review.
    Zeel Bhatia, Sunny Kumar, Sriram Seshadri.
      The connection between maternal microbiota and infant health has been greatly garnered interest for therapeutic purposes. The early resident microbiota perpetually exhibits much more flexibility as compared to that of the adults, and therefore, constant need of understanding the infant as well as maternal microbiota and their implications however has increased. In this review, we focus mainly on the diversity of overall maternal microbiota including the gut, vaginal, colostrum microbiota and how inflammatory markers fluctuate throughout the normal pregnancy as well in pregnancy with complications. The maternal body undergoes a cascade of physiological changes including hormonal, immunological and metabolic events to support the fetal development. These changes at the time of pregnancy have been correlated with alteration in the composition and diversity of maternal microbiota. Along with alteration in microbiome, the levels of circulatory cytokines fluctuate by complex network of inflammation, in order to prevent the fetal allograft throughout the pregnancy. The dynamic relationship of gut microbiota with the host and its immune system allows one to have greater insights of their role in pregnancy and newborn's health. Emerging evidence suggests that the vertical transmission of bacterial community from mother to newborn may begin in-utero which contributes in developing the immune system and infant gut microbiota.
    Keywords:  C-section; Cytokines; Gestational diabetes mellitus; Gut microbiota; Inflammation; Milk microbiota; Pregnancy; Trimester; Vaginal delivery
    DOI:  https://doi.org/10.1016/j.lfs.2024.122440
  25. Int Immunopharmacol. 2024 Jan 23. pii: S1567-5769(24)00076-6. [Epub ahead of print]128 111558
    Association between periodontitis and inflammatory comorbidities: The common role of innate immune cells, underlying mechanisms and therapeutic targets.
    Qibing Wu, Weijia Zhang, Yaqiong Lu, Hongxia Li, Yaru Yang, Fengxue Geng, Jinwen Liu, Li Lin, Yaping Pan, Chen Li.
      Periodontitis, which is related to various systemic diseases, is a chronic inflammatory disease caused by periodontal dysbiosis of the microbiota. Multiple factors can influence the interaction of periodontitis and associated inflammatory disorders, among which host immunity is an important contributor to this interaction. Innate immunity can be activated aberrantly because of the systemic inflammation induced by periodontitis. This aberrant activation not only exacerbates periodontal tissue damage but also impairs systemic health, triggering or aggravating inflammatory comorbidities. Therefore, innate immunity is a potential therapeutic target for periodontitis and associated inflammatory comorbidities. This review delineates analogous aberrations of innate immune cells in periodontitis and comorbid conditions such as atherosclerosis, diabetes, obesity, and rheumatoid arthritis. The mechanisms behind these changes in innate immune cells are discussed, including trained immunity and clonal hematopoiesis of indeterminate potential (CHIP), which can mediate the abnormal activation and myeloid-biased differentiation of hematopoietic stem and progenitor cells. Besides, the expansion of myeloid-derived suppressor cells (MDSCs), which have immunosuppressive and osteolytic effects on peripheral tissues, also contributes to the interaction between periodontitis and its inflammatory comorbidities. The potential treatment targets for relieving the risk of both periodontitis and systemic conditions are also elucidated, such as the modulation of innate immunity cells and mediators, the regulation of trained immunity and CHIP, as well as the inhibition of MDSCs' expansion.
    Keywords:  CHIP; Innate immunity; MDSCs; Periodontitis; Systemic inflammation; Trained immunity
    DOI:  https://doi.org/10.1016/j.intimp.2024.111558
  26. mSphere. 2024 Jan 23. e0070423
    Utilization of a Histoplasma capsulatum zinc reporter reveals the complexities of fungal sensing of metal deprivation.
    Logan T Blancett, Heather M Evans, Kathleen Candor, William R Buesing, Julio A Landero Figueroa, George S Deepe.
      Histoplasma capsulatum is a dimorphic fungal pathogen acquired via inhalation of soil-resident spores. Upon exposure to mammalian body temperatures, these fungal elements transform into yeasts that reside primarily within phagocytes. Macrophages (MΦ) provide a permissive environment for fungal replication until T cell-dependent immunity is engaged. MΦ activated by granulocyte macrophage colony stimulating factor (GM-CSF) induces metallothioneins (MTs) that bind zinc (Zn) and deprive yeast cells of labile Zn, thereby disabling fungal growth. Prior work demonstrated that the zinc transporter, ZRT2, was important for fungal survival in vivo. Hence, we constructed a yeast cell reporter strain that expresses green fluorescent protein (GFP) under control of the ZRT2 zinc-regulated promoter. This reporter accurately responds to a medium devoid of Zn. ZRT2 expression increased in GM-CSF, but not interferon-γ, stimulated MΦ. To examine the in vivo response, we infected mice with a reporter yeast strain and assessed ZRT2 expression at 0, 3, 7, and 14 days post-infection (dpi). ZRT2 expression minimally increased at 3 dpi and peaked at 7 dpi, corresponding with the onset of adaptive immunity. We discovered that the major MΦ populations that restrict Zn from the fungus are interstitial MΦ and exudate MΦ. Neutralizing GM-CSF blunted the control of infection but unexpectedly increased ZRT2 expression. This increase was dependent on another cytokine that activates MΦ to control H. capsulatum replication, M-CSF. These findings illustrate the reporter's ability to sense Zn in vitro and in vivo and correlate ZRT2 expression with GM-CSF and M-CSF activation of MΦ.IMPORTANCEPhagocytes use an arsenal of defenses to control the replication of Histoplasma yeasts, one of which is the limitation of trace metals. On the other hand, H. capsulatum combats metal restriction by upregulating metal importers such as the Zn importer ZRT2. This transporter contributes to H. capsulatum pathogenesis upon activation of adaptive immunity. We constructed a fluorescent ZRT2 transcriptional reporter to probe H. capsulatum Zn sensing during infection and exposed the role for M-CSF activation of macrophages when GM-CSF is absent. These data highlight the ways in which fungal pathogens sense metal deprivation in vivo and reveal the potential of metal-sensing reporters. The work adds a new dimension to study how intracellular pathogens sense and respond to the changing environments of the host.
    Keywords:  Histoplasma; cytokines; lung defense; macrophages; zinc
    DOI:  https://doi.org/10.1128/msphere.00704-23
  27. Nat Immunol. 2024 Jan 23.
    JAK1 hits a nerve.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01752-w
  28. Front Immunol. 2023 ;14 1333549
    Macrophage plasticity and function in cancer and pregnancy.
    Tingxuan Yin, Xinyi Li, Yanhong Li, Xingxing Zang, Lu Liu, Meirong Du.
      As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.
    Keywords:  immune microenvironment; immunosuppression; macrophages; maternal-fetal interface; plasticity; tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fimmu.2023.1333549
  29. Dis Model Mech. 2024 Jan 01. pii: dmm050541. [Epub ahead of print]17(1):
    Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis.
    Jasmin Scheurer, Birgit Sauer, Jule Focken, Martina Giampetraglia, Annika Jäger, Christian M Schürch, Bettina Weigelin, Birgit Schittek.
      Three-dimensional (3D) human skin equivalents have emerged as valuable tools in skin research, replacing animal experimentation and precluding the need for patient biopsies. In this study, we advanced 3D skin equivalents to model the inflammatory skin diseases atopic dermatitis and psoriasis by cytokine stimulation, and were successful in integrating TH1 T cells into skin models to develop an immunocompetent 3D psoriasis model. We performed in-depth histological and functional characterization of 3D skin equivalents and validated them in terms of tissue architecture, pathological changes, expression of antimicrobial peptides and Staphylococcus aureus colonization using 3D reconstruction by multiphoton microscopy and phenotyping by highly multiplexed 'co-detection by indexing' (CODEX) microscopy. We show that our skin equivalents have a structural architecture with a well-developed dermis and epidermis, thus resembling human skin. In addition, the skin models of atopic dermatitis and psoriasis show several phenotypic features of inflammatory skin disease, including disturbed epidermal differentiation and alterations in the expression of epidermal barrier genes and antimicrobial peptides, and can be reliably used to test novel treatment strategies. Therefore, these 3D equivalents will be a valuable tool in experimental dermatological research.
    Keywords:   Staphylococcus aureus ; 3D human skin model; Atopic dermatitis; Psoriasis
    DOI:  https://doi.org/10.1242/dmm.050541
  30. Mol Cell. 2024 Jan 17. pii: S1097-2765(24)00003-0. [Epub ahead of print]
    Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.
    Chuanlong Wang, Qingyi Chen, Siyuan Chen, Lijuan Fan, Zhending Gan, Muyang Zhao, Lexuan Shi, Peng Bin, Guan Yang, Xihong Zhou, Wenkai Ren.
      Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1β production, providing a potential inflammatory disease target.
    Keywords:  NAD(+); NLRP3; PHGDH; SIRT1; SIRT3; TLR4; acetylation; macrophage; serine
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.002
  31. Int J Mol Sci. 2024 Jan 18. pii: 1165. [Epub ahead of print]25(2):
    Recreating Human Skin In Vitro: Should the Microbiota Be Taken into Account?
    Andrea Galvan, Carlo Pellicciari, Laura Calderan.
      Skin plays crucial roles in the human body: besides protecting the organism from external threats, it acts as a thermal regulator, is responsible for the sense of touch, hosts microbial communities (the skin microbiota) involved in preventing the invasion of foreign pathogens, contains immunocompetent cells that maintain a healthy immunogenic/tolerogenic balance, and is a suitable route for drug administration. In the skin, four defense levels can be identified: besides the physical, chemical, and immune barriers that are inherent to the tissue, the skin microbiota (i.e., the numerous microorganisms living on the skin surface) provides an additional barrier. Studying the skin barrier function or the effects of drugs or cosmetic agents on human skin is a difficult task since snapshot evidence can only be obtained using bioptic samples where dynamic processes cannot properly be followed. To overcome these limitations, many different in vitro models of human skin have been developed that are characterized by diverse levels of complexity in terms of chemical, structural, and cellular composition. The aim of this review is to summarize and discuss the advantages and disadvantages of the different human skin models so far available and to underline how the insertion of a proper microbiota would positively impact an in vitro human skin model in an attempt to better mimic conditions in vivo.
    Keywords:  biological barriers; human skin; in vitro models; skin microbiota
    DOI:  https://doi.org/10.3390/ijms25021165
  32. Microbe. 2023 Dec;pii: 100023. [Epub ahead of print]1
    Integrating airway microbiome and blood proteomics data to identify multi-omic networks associated with response to pulmonary infection.
    Brenton I M Graham, J Kirk Harris, Edith T Zemanick, Brandie D Wagner.
      Host response to airway infections can vary widely. Cystic fibrosis (CF) pulmonary exacerbations provide an opportunity to better understand the interplay between respiratory microbes and the host. This study aimed to investigate the observed heterogeneity in airway infection recovery by analyzing microbiome and host response (i.e., blood proteome) data collected during the onset of 33 pulmonary infection events. We used sparse multiple canonical correlation network (SmCCNet) analysis to integrate these two types of -omics data along with a clinical measure of recovery. Four microbe-protein SmCCNet subnetworks at infection onset were identified that strongly correlate with recovery. Our findings support existing knowledge regarding CF airway infections. Additionally, we discovered novel microbe-protein subnetworks that are associated with recovery and merit further investigation.
    Keywords:  (SmCCNet) Analysis; Aptamers; Cystic fibrosis; Host response; Microbe-protein networks; Microbiome data integration; Pulmonary exacerbation; Sparse Multiple Canonical Correlation Network
    DOI:  https://doi.org/10.1016/j.microb.2023.100023
  33. Pharmaceutics. 2023 Dec 21. pii: 18. [Epub ahead of print]16(1):
    Lactobacillus johnsonii LJO02 (DSM 33828) Cell-Free Supernatant and Vitamin D Improve Wound Healing and Reduce Interleukin-6 Production in Staphylococcus aureus-Infected Human Keratinocytes.
    Paola Zanetta, Chiara Ballacchino, Diletta Francesca Squarzanti, Angela Amoruso, Marco Pane, Barbara Azzimonti.
      Methicillin-resistant biofilm-forming Staphylococcus spp. are found in about 25% of the overall cases of chronic wounds, which can undergo malignant degeneration and be associated with skin cancer. Although antimicrobial agents are clinically used to counteract pathogens and promote wound healing, they are increasingly ineffective against multi-drug resistant bacteria. Moreover, they can induce dysbiosis, which favors opportunistic pathogen infections and alters immune responses. Consequently, research on pathogen containment strategies is crucial. We aimed to evaluate the potential beneficial effect of Lactobacillus johnsonii LJO02 cell-free supernatant (CFS) and vitamin D, as single treatments or in combination, on cell viability, wound healing, and the pro-inflammatory interleukin-6 (IL-6) production of a Staphylococcus aureus-infected human immortalized keratinocyte cell line (HaCaT) in vitro model. The analysis showed that LJO02 CFS 20% v/v ratio and 100 nM vitamin D promoted infected cell viability and wound healing and significantly reduced IL-6 production. However, their effect was not synergic, since no significant difference between the single and combined treatments was observed. LJO02 CFS topic application and vitamin D supplementation could provide a valuable strategy for attenuating S. aureus-induced pathogenesis, promoting wound healing and opening new therapeutic strategies supporting the conventional approaches.
    Keywords:  Lactobacillus johnsonii; Staphylococcus aureus; cell viability; multi-drug resistance; probiotic cell-free supernatant; skin cancer; skin infection; skin inflammation; vitamin D; wound healing
    DOI:  https://doi.org/10.3390/pharmaceutics16010018
  34. Microorganisms. 2024 Jan 18. pii: 191. [Epub ahead of print]12(1):
    Exploring the Complexity of the Interaction between T. rubrum and S. aureus/S. epidermidis in the Formation of Polymicrobial Biofilms.
    Jenyffie A Belizario, Níura M Bila, Carolina O Vaso, Caroline B Costa-Orlandi, Matheus B Mendonça, Ana M Fusco-Almeida, Regina H Pires, Maria José S Mendes-Giannini.
      Dermatophytes associated with bacteria can lead to severe, difficult-to-treat infections and contribute to chronic infections. Trichophyton rubrum, Staphylococcus aureus, and Staphylococcus epidermidis can form biofilms influenced by nutrient availability. This study investigated biofilm formation by these species by utilizing diverse culture media and different time points. These biofilms were studied through scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), biomass, metabolic activity, and colony-forming units (CFUs). The results revealed that mixed biofilms exhibited high biomass and metabolic activity when cultivated in the brain heart infusion (BHI) medium. Both bacterial species formed mature biofilms with T. rubrum within 72 h, irrespective of media. The timing of bacterial inoculation was pivotal in influencing biomass and metabolic activity. T. rubrum's development within mixed biofilms depended on bacterial addition timing, while pre-adhesion influenced fungal growth. Bacterial communities prevailed initially, while fungi dominated later in the mixed biofilms. CLSM revealed 363 μm thick T. rubrum biofilms with septate, well-developed hyphae; S. aureus (177 μm) and S. epidermidis (178 μm) biofilms showed primarily cocci. Mixed biofilms matched T. rubrum's thickness when associated with S. epidermidis (369 μm), with few hyphae initially. Understanding T. rubrum and Staphylococcal interactions in biofilms advances antimicrobial resistance and disease progression knowledge.
    Keywords:  Staphylococcus aureus; Staphylococcus epidermidis; Trichophyton rubrum; biofilms; dermatophytes; dual-species biofilms
    DOI:  https://doi.org/10.3390/microorganisms12010191
  35. Biomedicines. 2024 Jan 08. pii: 128. [Epub ahead of print]12(1):
    An In Vitro Model to Assess Early Immune Markers Following Co-Exposure of Epithelial Cells to Carbon Black (Nano)Particles in the Presence of S. aureus: A Role for Stressed Cells in Toxicological Testing.
    Scott Brown, Stephen J Evans, Michael J Burgum, Kirsty Meldrum, Jack Herridge, Blessing Akinbola, Llinos G Harris, Rowena Jenkins, Shareen H Doak, Martin J D Clift, Thomas S Wilkinson.
      The exposure of human lung and skin to carbon black (CB) is continuous due to its widespread applications. Current toxicological testing uses 'healthy' cellular systems; however, questions remain whether this mimics the everyday stresses that human cells are exposed to, including infection. Staphylococcus aureus lung and skin infections remain prevalent in society, and include pneumonia and atopic dermatitis, respectively, but current in vitro toxicological testing does not consider infection stress. Therefore, investigating the effects of CB co-exposure in 'stressed' infected epithelial cells in vitro may better approximate true toxicity. This work aims to study the impact of CB exposure during Staphylococcus aureus infection stress in A549 (lung) and HaCaT (skin) epithelial cells. Physicochemical characterisation of CB confirmed its dramatic polydispersity and potential to aggregate. CB significantly inhibited S. aureus growth in cell culture media. CB did not induce cytokines or antimicrobial peptides from lung and skin epithelial cells, when given alone, but did reduce HaCaT and A549 cell viability to 55% and 77%, respectively. In contrast, S. aureus induced a robust interleukin (IL)-8 response in both lung and skin epithelial cells. IL-6 and human beta defensin (hβD)-2 could only be detected when cells were stimulated with S. aureus with no decreases in cell viability. However, co-exposure to CB (100 µg/mL) and S. aureus resulted in significant inhibition of IL-8 (compared to S. aureus alone) without further reduction in cell viability. Furthermore, the same co-exposure induced significantly more hβD-2 (compared to S. aureus alone). This work confirms that toxicological testing in healthy versus stressed cells gives significantly different responses. This has significant implications for toxicological testing and suggests that cell stresses (including infection) should be included in current models to better represent the diversity of cell viabilities found in lung and skin within a general population. This model will have significant application when estimating CB exposure in at-risk groups, such as factory workers, the elderly, and the immunocompromised.
    Keywords:  A549; HaCaT; Staphylococcus aureus; carbon black (nano)particles; cytokines; epithelial cells; in vitro co-exposure models; infection; particle exposure
    DOI:  https://doi.org/10.3390/biomedicines12010128
  36. Sci Rep. 2024 01 20. 14(1): 1799
    Surfactant protein D prevents mucin overproduction in airway goblet cells via SIRPα.
    Kentaro Hata, Kazuya Tsubouchi, Kunihiro Suzuki, Daisuke Eto, Hiroyuki Ando, Toyoshi Yanagihara, Keiko Kan-O, Isamu Okamoto.
      Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air-liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.
    DOI:  https://doi.org/10.1038/s41598-024-52328-5
  37. Curr Oncol. 2023 Dec 28. 31(1): 168-182
    Mechanisms and Potential Clinical Implications of Oral Microbiome in Oral Squamous Cell Carcinoma.
    Jingyi Wang, Bo Gao.
      Microorganisms in the oral cavity are abundant in the human body. At present, more than 700 species of oral microorganisms have been identified. Recently, a lot of literature has indicated that the oral microbiota plays an important role in the occurrence, development, and prognosis of oral squamous cell carcinoma (OSCC) through various mechanisms. And researchers are now trying to utilize oral microbiota in cancer diagnosis and treatment. However, few articles systematically summarize the effects of oral microbes in the diagnosis, treatment, and disease outcomes of oral cancer. Herein, we made a summary of the microbial changes at cancerous sites and placed more emphasis on the mechanisms by which the oral microbiome promotes cancerization. Moreover, we aimed to find out the clinical value of the oral microbiome in OSCC.
    Keywords:  immunity; inflammation; oral microbiome; oral potentially malignant disorders; oral squamous cell carcinoma
    DOI:  https://doi.org/10.3390/curroncol31010011
  38. Int J Biol Sci. 2024 ;20(3): 968-986
    SGK1 aggravates idiopathic pulmonary fibrosis by triggering H3k27ac-mediated macrophage reprogramming and disturbing immune homeostasis.
    Jianzhi Wu, Liping Gong, Yijie Li, Tiegang Liu, Rong Sun, Kexin Jia, Runping Liu, Fei Dong, Xiaohong Gu, Xiaojiaoyang Li.
      Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic matrix deposition and irreversible aberrant tissue remodeling. Their mechanisms of action are associated with the activation of macrophages and a disturbed immune environment. We aim to determine how these activated macrophages influenced the pathogenesis of pulmonary fibrosis. We found the fibrotic areas of IPF patients contained more serum and glucocorticoid-induced kinase 1 (SGK1)-positive and M2-type macrophages. Similarly, bleomycin (BLM)+LPS significantly triggered high expression of SGK1 in the IPF mice, accompanied by destroyed lung structure and function, increased fibrosis markers and disturbed immune microenvironment. Mechanistically, SGK1 markedly promoted the reprogramming of M2-type macrophages in fibrotic lungs by triggering glycogen synthase kinase 3beta (GSK3β)-tat-interacting protein 60 (TIP60)- histone-3 lysine-27 acetylation (H3K27ac) signalings, which further released chemokine (C-C motif) ligand 9 (CCL9) to attract Th17 cells and delivered TGF-β to fibroblasts for synergistically destroying immune microenvironment, which was largely reversed by macrophage depletion in mice. We took macrophages as the entry point to deeply analyze IPF pathogenesis and further provided insights for the development of novel drugs represented by SGK1.
    Keywords:  H3K27ac; SGK1; immune homeostasis; macrophage reprogramming; pulmonary fibrosis
    DOI:  https://doi.org/10.7150/ijbs.90808
  39. Cell Biosci. 2024 Jan 20. 14(1): 11
    NF-κB RelA is a cell-intrinsic metabolic checkpoint restricting glycolysis.
    Liwen Li, Lei Han, Zhaoxia Qu.
      An intrinsic link between metabolism and function in immune cells, and in particular macrophages, has been well established recently. However, the molecular mechanisms controlling the metabolic switch in these sentinel cells for their integral roles in host defense, inflammation, homeostasis, and pathogenesis remain largely unknown. Here, we identify the master transcription factor NF-κB RelA as a vital cell-intrinsic checkpoint restricting aerobic glycolysis to favor mitochondrial oxidative phosphorylation (OXPHOS) and "M2" activation (alternative anti-inflammatory and pro-tumorigenic activation, in contrast to classical pro-inflammatory and anti-tumor M1 activation) of macrophages under oncogenic stress. RelA specific knockdown or genetic deletion in macrophages causes metabolism to shift away from OXPHOS toward glycolysis, resulting in drastically decreased oxygen consumption but significantly increased lactate and ATP production. The metabolic change in RelA deficient cells is associated with the decrease in the expressions of the OXPHOS gene SCO2 as well as the M2 marker and function genes arginase-1 and VEGF. These data suggest that RelA induces SCO2 expression to enhance OXPHOS and restrict glycolysis in macrophages for their pro-tumorigenic activation.
    Keywords:  Glycolysis; Macrophages; Metabolic checkpoint; Metabolic switch; Metabolism; NF-κB; Oxidative phosphorylation; RelA/p65
    DOI:  https://doi.org/10.1186/s13578-024-01196-7
  40. bioRxiv. 2024 Jan 04. pii: 2024.01.02.573939. [Epub ahead of print]
    Stably-Inverted Apical-Out Human Upper Airway Organoids for SARS-CoV-2 Infection and Therapeutic Testing.
    Ji-Hoon Lee, Julia C LeCher, Eric Parigoris, Noriyuki Shinagawa, Jason Sentosa, Candela Manfredi, Shu Ling Goh, Ramyani De, Sijia Tao, Keivan Zandi, Franck Amblard, Eric J Sorscher, Jason R Spence, Rabindra Tirouvanziam, Raymond F Schinazi, Shuichi Takayama.
      Apical-out organoids produced through eversion triggered by extra-organoid extracellular matrix (ECM) removal or degradation are generally small, structurally variable, and limited for viral infection and therapeutics testing. This work describes ECM-encapsulating, stably-inverted apical-out human upper airway organoids (AORBs) that are large (∼500 µm diameter), consistently spherical, recapitulate in vivo -like cellular heterogeneity, and maintain their inverted morphology for over 60 days. Treatment of AORBs with IL-13 skews differentiation towards goblet cells and the apical-out geometry allows extra-organoid mucus collection. AORB maturation for 14 days induces strong co-expression of ACE2 and TMPRSS2 to allow high-yield infection with five SARS-CoV-2 variants. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds [remdesivir, bemnifosbuvir (AT-511), and nirmatrelvir] shows AORB antiviral assays to be comparable to gold-standard air-liquid interface cultures, but with higher throughput (∼10-fold) and fewer cells (∼100-fold). While this work focuses on SARS-CoV-2 applications, the consistent AORB shape and size, and one-organoid-per-well modularity broadly impacts in vitro human cell model standardization efforts in line with economic imperatives and recently updated FDA regulation on therapeutic testing.
    DOI:  https://doi.org/10.1101/2024.01.02.573939
  41. Microbiology (Reading). 2024 Jan;170(1):
    Time-lapse mesoscopy of Candida albicans and Staphylococcus aureus dual-species biofilms reveals a structural role for the hyphae of C. albicans in biofilm formation.
    Katherine J Baxter, Fiona A Sargison, J Ross Fitzgerald, Gail McConnell, Paul A Hoskisson.
      Polymicrobial infection with Candida albicans and Staphylococcus aureus may result in a concomitant increase in virulence and resistance to antimicrobial drugs. This enhanced pathogenicity phenotype is mediated by numerous factors, including metabolic processes and direct interaction of S. aureus with C. albicans hyphae. The overall structure of biofilms is known to contribute to their recalcitrance to treatment, although the dynamics of direct interaction between species and how it contributes to pathogenicity is poorly understood. To address this, a novel time-lapse mesoscopic optical imaging method was developed to enable the formation of C. albicans/S. aureus whole dual-species biofilms to be followed. It was found that yeast-form or hyphal-form C. albicans in the biofilm founder population profoundly affects the structure of the biofilm as it matures. Different sub-populations of C. albicans and S. aureus arise within each biofilm as a result of the different C. albicans morphotypes, resulting in distinct sub-regions. These data reveal that C. albicans cell morphology is pivotal in the development of global biofilm architecture and the emergence of colony macrostructures and may temporally influence synergy in infection.
    Keywords:  Candida albicans; Staphylococcus aureus; biofilm; co-infection
    DOI:  https://doi.org/10.1099/mic.0.001426
  42. bioRxiv. 2024 Jan 10. pii: 2024.01.10.575018. [Epub ahead of print]
    Highly-resolved within-species dynamics in the human facial skin microbiome.
    Jacob S Baker, Evan Qu, Christopher P Mancuso, A Delphine Tripp, Arolyn Conwill, Tami D Lieberman.
      Human facial skin microbiomes (FSMs) on adults are dominated by just two bacterial species, Cutibacterium acnes and Staphylococcus epidermidis. Underlying this apparent simplicity, each FSM harbors multiple strains of both species whose assembly dynamics on individuals are unknown. Here, we use 4,055 isolate genomes and 360 metagenomes to trace the dynamics of strains on individuals and their transmission. Strains are shared amongst family members of all ages, but each individual harbors unique strain consortia. Strain stability changes upon formation of the adult-type FSM: S. epidermidis lineage turnover slows, and the rate of C. acnes colonization increases before stabilizing, suggesting this transitional window could facilitate engraftment of therapeutic strains. Our work reveals previously undetectable community dynamics and informs the design of therapeutic interventions.
    One-Sentence Summary: Previously undetectable gain and loss of individual strains underlies the species stability of important microbiome bacteria.
    DOI:  https://doi.org/10.1101/2024.01.10.575018
  43. Nat Immunol. 2024 Jan 23.
    Mucosal boosting.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-024-01751-x
  44. Am J Physiol Lung Cell Mol Physiol. 2024 Jan 22.
    A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues.
    Zhijian He, Catherine Chu, Riley Dickson, Kenichi Okuda, Liheng Cai.
      Since its invention in the late 1980s, the air-liquid-interface (ALI) culture system has been the standard in vitro model for studying human airway biology and pulmonary diseases. However, in a conventional ALI system, cells are cultured on a porous plastic membrane that is much stiffer than human airway tissues. Here, we develop a gel-ALI culture system by simply coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We determine the optimum gel thickness that does not impair the transport of nutrients and biomolecules essential to cell growth. We show that the gel-ALI system allows human bronchial epithelial cells (HBECs) to proliferate and differentiate into a pseudostratified epithelium. Further, we discover that HBECs migrate significantly faster on hydrogel substrates with stiffness matching that of fibrotic lung tissues, highlighting the importance of mechanical cues in human airway remodeling. The developed gel-ALI system provides a facile approach to studying the effects of mechanical cues in human airway biology and in modeling pulmonary diseases.
    Keywords:  air-liquid-interface; cell differentiation; collective cell migration; human bronchial epithelia; substrate stiffness
    DOI:  https://doi.org/10.1152/ajplung.00153.2023
  45. Microb Pathog. 2024 Jan 23. pii: S0882-4010(24)00024-X. [Epub ahead of print] 106557
    The role of the Notch signaling pathway in bacterial infectious diseases.
    Zhengwei Yin, Yuejie Zhu, Juan Shi, Yueyue He, Fengbo Zhang.
      The Notch signaling pathway is the most crucial link in the normal operation and maintenance of physiological functions of mammalian life processes. Notch receptors interact with ligands and this leads to three cleavages and goes on to enter the nucleus to initiate the transcription of target genes. The Notch signaling pathway deeply participates in the differentiation and function of various cells, including immune cells. Recent studies indicate that the outcomes of Notch signaling are changeable and highly dependent on different bacterial infection. The Notch signaling pathway plays a different role in promoting and inhibiting bacterial infection. In this review, we focus on the latest research findings of the Notch signaling pathway in bacterial infectious diseases. The Notch signaling pathway is critically involved in a variety of development processes of immunosuppression of different APCs. The Notch signaling pathway leads to functional changes in epithelial cells to aggravate tissue damage. Specifically, we illustrate the regulatory mechanism of the Notch signaling pathway in various bacterial infections, such as Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis, Mycobacterium leprae, Helicobacter pylori, Klebsiella pneumoniae, Bacillus subtilis, Staphylococcus aureus, Ehrlichia chaffeensis and sepsis. Collectively, this review will not only help beginners intuitively and systematically understand the Notch signaling pathway in bacterial infectious diseases but also help experts to generate fresh insight in this field.
    Keywords:  Bacteria; Immune cells; Infection; Notch
    DOI:  https://doi.org/10.1016/j.micpath.2024.106557
  46. Elife. 2024 Jan 26. pii: e90091. [Epub ahead of print]13
    Variation in the basal immune state and implications for disease.
    Aisha Souquette, Paul G Thomas.
      Analysis of pre-existing immunity and its effects on acute infection often focus on memory responses associated with a prior infectious exposure. However, memory responses occur in the context of the overall immune state and leukocytes must interact with their microenvironment and other immune cells. Thus, it is important to also consider non-antigen-specific factors which shape the composite basal state and functional capacity of the immune system, termed here as I0 ('I naught'). In this review, we discuss the determinants of I0. Utilizing influenza virus as a model, we then consider the effect of I0 on susceptibility to infection and disease severity. Lastly, we outline a mathematical framework and demonstrate how researchers can build and tailor models to specific needs. Understanding how diverse factors uniquely and collectively impact immune competence will provide valuable insights into mechanisms of immune variation, aid in screening for high-risk populations, and promote the development of broadly applicable prophylactic and therapeutic treatments.
    Keywords:  chronic co-infection; correlate of protection; correlate of severity; determinants of immunity; heterologous infection; heterosubtypic; immune memory; immunology; inflammation; influenza
    DOI:  https://doi.org/10.7554/eLife.90091
  47. Front Cell Infect Microbiol. 2023 ;13 1306430
    In vitro antibacterial activity of antiretroviral drugs on key commensal bacteria from the human microbiota.
    Elisa Rubio-Garcia, Núria Ferrando, Núria Martin, Clara Ballesté-Delpierre, Jose M Miró, Roger Paredes, Climent Casals-Pascual, Jordi Vila.
       Introduction: Antiretroviral therapy has improved life expectancy in HIV-infected patients. However, people living with HIV under antiretroviral therapy are at higher risks of developing chronic complications and acquiring multidrug resistant bacteria than healthy population. These factors have been associated with shifts in gut microbiome composition and immune activation. It is unclear how antiretroviral drugs affect gut microbiota composition, but it has been observed that antiretroviral treatment is not able to fully restore gut health after HIV infection. Additionally, some antiretroviral drugs have shown antibacterial activity suggesting that these drugs could have a direct impact on the human microbiome composition.
    Methods: We determined the in vitro antibacterial activity of 16 antiretroviral drugs against a set of key clinically relevant and human commensal bacterial strains.
    Results: Our results demonstrate that 5 antiretroviral drugs have in vitro antibacterial activity against gut and vaginal human commensal bacteria. Zidovudine has antibacterial activity against Escherichia coli, Klebsiella pneumoniae and Prevotella bivia, abacavir against Gardnerella vaginalis, efavirenz against G. vaginalis and P. bivia and bictegravir against Enterococcus spp. and G. vaginalis. Moreover, we describe for the first time that elvitegravir has antibacterial activity against G. vaginalis and P. bivia and, most importantly, against vancomycin-resistant Enterococcus spp. and methicillin-resistant Staphylococcus aureus strains with MIC values of 4-16 and 4 µg/mL, respectively showing high level of effectiveness against the tested multidrug-resistant bacteria.
    Discussion: Our results underscore that some antiretroviral drugs may influence the human microbiota composition. In addition, we report the potential use of elvitegravir to treat multidrug-resistant Gram-positive bacteria warranting the need of clinical studies to repurpose this antiretroviral drug.
    Keywords:  antibacterial activity; antiretroviral therapy; elvitegravir repurposing; human commensal bacteria; multidrug resistant bacteria
    DOI:  https://doi.org/10.3389/fcimb.2023.1306430
  48. Front Immunol. 2023 ;14 1354723
    Editorial: Glycans: molecules at the interface of immunity and disease.
    Stevan A Springer, Shoib Sawar Siddiqui.
      
    Keywords:  cancer; glycans; glycobiology; immunity; infection; inflammation; lectins; molecular evolution
    DOI:  https://doi.org/10.3389/fimmu.2023.1354723
  49. J Appl Microbiol. 2024 Jan 24. pii: lxae018. [Epub ahead of print]
    Lactobacillus rhamnosus dampens cytokine and chemokine secretion from primary human nasal epithelial cells infected with rhinovirus.
    Tejasri Yarlagadda, Yanshan Zhu, Natale Snape, Alison Carey, Emily Bryan, Diane Maresco-Pennisi, Andrea Coleman, Anders Cervin, Kirsten Spann.
       AIMS: To investigate the effect of Lactobacillus rhamnosus on viral replication and cellular response to human rhinovirus (HRV) infection including the secretion of antiviral and inflammatory mediators from well-differentiated nasal epithelial cells (WD-NECs).
    METHODS AND RESULTS: The WD-NECs from healthy adult donors (N = 6) were cultured in vitro, exposed to different strains of L. rhamnosus (D3189, D3160 or LB21), and infected with HRV (RV-A16) after 24 hours. Survival and adherence capacity of L. rhamnosus in a NEC environment was confirmed using CFSE-labelled isolates, immunofluorescent staining and confocal microscopy. Shed virus and viral replication were quantified using TCID50 assays and RT-qPCR, respectively. Cytotoxicity was measured by lactate dehydrogenase (LDH) activity. Pro-inflammatory mediators were measured by multiplex immunoassay, and interferon (IFN)-λ1/3 was measured using a standard ELISA kit. L. rhamnosus was able to adhere to and colonise WD-NECs prior to RV-A16 infection. L. rhamnosus did not affect shed RV-A16, viral replication or RV-A16-induced IFN-λ1/3 production, or LDH release. Pre-exposure to L. rhamnosus, particularly D3189, reduced the secretion of RV-A16-induced pro-inflammatory mediators by WD-NECs.
    CONCLUSIONS: These findings demonstrate that L. rhamnosus differentially modulate RV-A16 induced innate inflammatory immune responses in primary NECs from healthy adults.
    Keywords:  Lactobacilli; human rhinovirus; immunomodulation; inflammation; innate immunity; nasal epithelium
    DOI:  https://doi.org/10.1093/jambio/lxae018
  50. Pathogens. 2023 Dec 31. pii: 42. [Epub ahead of print]13(1):
    Therapeutic Effects of IL-1RA against Acute Bacterial Infections, including Antibiotic-Resistant Strains.
    Ines Ambite, Thi Hien Tran, Daniel S C Butler, Michele Cavalera, Murphy Lam Yim Wan, Shahram Ahmadi, Catharina Svanborg.
      Innate immunity is essential for the anti-microbial defense, but excessive immune activation may cause severe disease. In this study, immunotherapy was shown to prevent excessive innate immune activation and restore the anti-bacterial defense. E. coli-infected Asc-/- mice develop severe acute cystitis, defined by IL-1 hyper-activation, high bacterial counts, and extensive tissue pathology. Here, the interleukin-1 receptor antagonist (IL-1RA), which inhibits IL-1 hyper-activation in acute cystitis, was identified as a more potent inhibitor of inflammation and NK1R- and substance P-dependent pain than cefotaxime. Furthermore, IL-1RA treatment inhibited the excessive innate immune activation in the kidneys of infected Irf3-/- mice and restored tissue integrity. Unexpectedly, IL-1RA also accelerated bacterial clearance from infected bladders and kidneys, including antibiotic-resistant E. coli, where cefotaxime treatment was inefficient. The results suggest that by targeting the IL-1 response, control of the innate immune response to infection may be regained, with highly favorable treatment outcomes, including infections caused by antibiotic-resistant strains.
    Keywords:  IL-1; IL-1 receptor antagonist; acute cystitis; acute pyelonephritis; antibiotic resistance; immunotherapy; infection; substance P; urinary tract infection; uropathogenic Escherichia coli
    DOI:  https://doi.org/10.3390/pathogens13010042
  51. Am J Respir Crit Care Med. 2024 Jan 23.
    Pharmacological Improvement of CFTR Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.
    Jennifer Loske, Mirjam Völler, Sören Lukassen, Mirjam Stahl, Loreen Thürmann, Anke Seegebarth, Jobst Röhmel, Sebastian Wisniewski, Marey Messingschlager, Stephan Lorenz, Sven Klages, Roland Eils, Irina Lehmann, Marcus A Mall, Simon Y Graeber, Saskia Trump.
       RATIONALE: Pharmacological improvement of CFTR function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes to patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular level in the airways of CF patients remain unknown.
    OBJECTIVES: To investigate effects of ETI on the transcriptiome of nasal epithelial and immune cells from children with CF at the single cell level.
    METHODS: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and three months after initiation of ETI, subjected to scRNA-seq and compared to swabs from 12 age-matched healthy children.
    MEASUREMENTS AND MAIN RESULTS: Proportions of CFTR-positive cells were decreased in epithelial basal, club and goblet cells, but not in ionocytes from children with CF at baseline and were restored on ETI therapy to near healthy levels. Single cell transcriptomics revealed an impaired interferon signalling and reduced expression of MHC I and II encoding genes in epithelial cells of CF children at baseline, which was partially restored by ETI. Additionally, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages.
    CONCLUSIONS: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.
    Keywords:  CFTR modulation; airway inflammation; cystic fibrosis; epithelial homeostasis; single cell RNA sequencing
    DOI:  https://doi.org/10.1164/rccm.202310-1836OC
  52. Front Med (Lausanne). 2023 ;10 1265544
    Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.
    Jian-Lan Hua, Zi-Feng Yang, Qi-Jian Cheng, Yao-Pin Han, Zheng-Tu Li, Ran-Ran Dai, Bin-Feng He, Yi-Xing Wu, Jing Zhang.
       Introduction: Considering the role of bacteria in the onset of acute exacerbation of COPD (AECOPD), we hypothesized that the use of influenza-Streptococcus pneumoniae vaccination, oral probiotics or inhaled amikacin could prevent AECOPD.
    Methods: In this pilot prospective, muti-central, randomized trial, moderate-to-very severe COPD subjects with a history of moderate-to-severe exacerbations in the previous year were enrolled and assigned in a ratio of 1:1:1:1 into 4 groups. All participants were managed based on the conventional treatment recommended by GOLD 2019 report for 3 months, with three groups receiving additional treatment of inhaled amikacin (0.4 g twice daily, 5-7 days monthly for 3 months), oral probiotic Lactobacillus rhamnosus GG (1 tablet daily for 3 months), or influenza-S. pneumoniae vaccination. The primary endpoint was time to the next onset of moderate-to-severe AECOPD from enrollment. Secondary endpoints included CAT score, mMRC score, adverse events, and survival in 12 months.
    Results: Among all 112 analyzed subjects (101 males, 96 smokers or ex-smokers, mean ± SD age 67.19 ± 7.39 years, FEV1 41.06 ± 16.09% predicted), those who were given dual vaccination (239.7 vs. 198.2 days, p = 0.044, 95%CI [0.85, 82.13]) and oral probiotics (248.8 vs. 198.2 days, p = 0.017, 95%CI [7.49, 93.59]) had significantly delayed onset of next moderate-to-severe AECOPD than those received conventional treatment only. For subjects with high symptom burden, the exacerbations were significantly delayed in inhaled amikacin group as compared to the conventional treatment group (237.3 vs. 179.1 days, p = 0.009, 95%CI [12.40,104.04]). The three interventions seemed to be safe and well tolerated for patient with stable COPD.
    Conclusion: The influenza-S. pneumoniae vaccine and long-term oral probiotic LGG can significantly delay the next moderate-to-severe AECOPD. Periodically amikacin inhalation seems to work in symptomatic patients. The findings in the current study warrants validation in future studies with microbiome investigation.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT03449459.
    Keywords:  amikacin; chronic obstructive pulmonary disease; inhaled antibiotics; probiotic; vaccination
    DOI:  https://doi.org/10.3389/fmed.2023.1265544
  53. Nat Commun. 2024 Jan 25. 15(1): 744
    Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients.
    Erik Duijvelaar, Jack Gisby, James E Peters, Harm Jan Bogaard, Jurjan Aman.
      The pathobiology of respiratory failure in COVID-19 consists of a complex interplay between viral cytopathic effects and a dysregulated host immune response. In critically ill patients, imatinib treatment demonstrated potential for reducing invasive ventilation duration and mortality. Here, we perform longitudinal profiling of 6385 plasma proteins in 318 hospitalised patients to investigate the biological processes involved in critical COVID-19, and assess the effects of imatinib treatment. Nine proteins measured at hospital admission accurately predict critical illness development. Next to dysregulation of inflammation, critical illness is characterised by pathways involving cellular adhesion, extracellular matrix turnover and tissue remodelling. Imatinib treatment attenuates protein perturbations associated with inflammation and extracellular matrix turnover. These proteomic alterations are contextualised using external pulmonary RNA-sequencing data of deceased COVID-19 patients and imatinib-treated Syrian hamsters. Together, we show that alveolar capillary barrier disruption in critical COVID-19 is reflected in the plasma proteome, and is attenuated with imatinib treatment. This study comprises a secondary analysis of both clinical data and plasma samples derived from a clinical trial that was registered with the EU Clinical Trials Register (EudraCT 2020-001236-10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001236-10/NL ) and Netherlands Trial Register (NL8491, https://www.trialregister.nl/trial/8491 ).
    DOI:  https://doi.org/10.1038/s41467-024-44986-w
  54. Immunometabolism (Cobham). 2024 Jan;6(1): e00038
    Inflammaging and fatty acid oxidation in monocytes and macrophages.
    Victor Kruglov, In Hwa Jang, Christina D Camell.
      Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5' AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.
    Keywords:  aging; cytokines; fatty acid oxidation; inflammaging; inflammasome; inflammation; lipid droplets; macrophages; metabolic disease; microglia; monocytes
    DOI:  https://doi.org/10.1097/IN9.0000000000000038
  55. Front Immunol. 2023 ;14 1347401
    Cell death proteins in sepsis: key players and modern therapeutic approaches.
    Chloe S Yang, Craig M Coopersmith, John D Lyons.
      Cell death proteins play a central role in host immune signaling during sepsis. These interconnected mechanisms trigger cell demise via apoptosis, necroptosis, and pyroptosis while also driving inflammatory signaling. Targeting cell death mediators with novel therapies may correct the dysregulated inflammation seen during sepsis and improve outcomes for septic patients.
    Keywords:  apoptosis; cell death; inflammation; necroptosis; pyroptosis; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2023.1347401
  56. J Clin Med. 2024 Jan 08. pii: 346. [Epub ahead of print]13(2):
    Advances and Applications of Lung Organoids in the Research on Acute Respiratory Distress Syndrome (ARDS).
    Xingwu Zhang, Longxiang Su, Pan Pan.
      Acute Respiratory Distress Syndrome (ARDS) is a sudden onset of lung injury characterized by bilateral pulmonary edema, diffuse inflammation, hypoxemia, and a low P/F ratio. Epithelial injury and endothelial injury are notable in the development of ARDS, which is more severe under mechanical stress. This review explains the role of alveolar epithelial cells and endothelial cells under physiological and pathological conditions during the progression of ARDS. Mechanical injury not only causes ARDS but is also a side effect of ventilator-supporting treatment, which is difficult to model both in vitro and in vivo. The development of lung organoids has seen rapid progress in recent years, with numerous promising achievements made. Multiple types of cells and construction strategies are emerging in the lung organoid culture system. Additionally, the lung-on-a-chip system presents a new idea for simulating lung diseases. This review summarizes the basic features and critical problems in the research on ARDS, as well as the progress in lung organoids, particularly in the rapidly developing microfluidic system-based organoids. Overall, this review provides valuable insights into the three major factors that promote the progression of ARDS and how advances in lung organoid technology can be used to further understand ARDS.
    Keywords:  Acute Respiratory Distress Syndrome (ARDS); lung organoid; microfluidic system; pluripotent stem cell
    DOI:  https://doi.org/10.3390/jcm13020346
  57. Int J Biol Macromol. 2024 Jan 20. pii: S0141-8130(24)00410-0. [Epub ahead of print]260(Pt 2): 129607
    A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.
    Di Wu, Kejia Zhang, Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Kaifeng Guan, Fei Sun, Chunjie Huang.
      Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one‑carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.
    Keywords:  Cancer therapeutics; Mitochondrial-associated disorders; Neurodegenerative pathologies; Serine; Serine metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129607
  58. Am J Respir Crit Care Med. 2024 Jan 25.
    Leveraging Microbiome Composition Variability for Precision Medicine in Idiopathic Pulmonary Fibrosis.
    Hajime Fujimoto, Corina N D'Alessandro-Gabazza, Taro Yasuma, Esteban C Gabazza, Osamu Hataji, Tetsu Kobayashi.
      
    Keywords:  Biomarkers; Dysbiosis; Idiopathic pulmonary fibrosis; Microbiome; Survival
    DOI:  https://doi.org/10.1164/rccm.202310-1899LE
  59. mBio. 2024 Jan 26. e0254023
    MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections.
    Christian Roehrig, Markus Huemer, Dominique Lorgé, Fabienne Arn, Nadine Heinrich, Lavanja Selvakumar, Lynn Gasser, Patrick Hauswirth, Chun-Chi Chang, Tiziano A Schweizer, Fritz Eichenseher, Steffi Lehmann, Annelies S Zinkernagel, Mathias Schmelcher.
      Bacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin-resistant Staphylococcus aureus is one of the deadliest pathogens and a high-priority pathogen according to the World Health Organization. Peptidoglycan hydrolases (PGHs) of phage origin have been postulated as a new class of antimicrobials for the treatment of bacterial infections, with a novel mechanism of action and no known resistances. The modular architecture of PGHs permits the creation of chimeric PGH libraries. In this study, the chimeric enzyme MEndoB was selected from a library of staphylococcal PGHs based on its rapid and sustained activity against staphylococci in human serum. The benefit of the presented screening approach was illustrated by the superiority of MEndoB in a head-to-head comparison with other PGHs intended for use against staphylococcal bacteremia. MEndoB displayed synergy with antibiotics and rapid killing in human whole blood with complete inhibition of re-growth over 24 h at low doses. Successful treatment of S. aureus-infected zebrafish larvae with MEndoB provided evidence for its in vivo effectiveness. This was further confirmed in a lethal systemic mouse infection model in which MEndoB significantly reduced S. aureus loads and tumor necrosis factor alpha levels in blood in a dose-dependent manner, which led to increased survival of the animals. Thus, the thorough lead candidate selection of MEndoB resulted in an outstanding second-generation PGH with in vitro, ex vivo, and in vivo results supporting further development.IMPORTANCEOne of the most pressing challenges of our era is the rising occurrence of bacteria that are resistant to antibiotics. Staphylococci are prominent pathogens in humans, which have developed multiple strategies to evade the effects of antibiotics. Infections caused by these bacteria have resulted in a high burden on the health care system and a significant loss of lives. In this study, we have successfully engineered lytic enzymes that exhibit an extraordinary ability to eradicate staphylococci. Our findings substantiate the importance of meticulous lead candidate selection to identify therapeutically promising peptidoglycan hydrolases with unprecedented activity. Hence, they offer a promising new avenue for treating staphylococcal infections.
    Keywords:  MRSA; Staphylococcus aureus; antibiotic resistance; antibiotics; bacteremia; bacteriophage; endolysin; peptidoglycan hydrolase; protein therapeutics; staphylococci
    DOI:  https://doi.org/10.1128/mbio.02540-23
  60. Front Cell Infect Microbiol. 2023 ;13 1290914
    Possible modulating functions of probiotic Lactiplantibacillus plantarum in particulate matter-associated pulmonary inflammation.
    Nishant Gupta, N S Abd El-Gawaad, Suhad Ali Osman Abdallah, M Al-Dossari.
      Pulmonary disease represents a substantial global health burden. Increased air pollution, especially fine particulate matter (PM2.5) is the most concerned proportion of air pollutants to respiratory health. PM2.5 may carry or combine with other toxic allergens and heavy metals, resulting in serious respiratory allergies and anaphylactic reactions in the host. Available treatment options such as antihistamines, steroids, and avoiding allergens/dust/pollutants could be limited due to certain side effects and immense exposure to air pollutants, especially in most polluted countries. In this mini-review, we summarized how PM2.5 triggers respiratory hyperresponsiveness and inflammation, and the probiotic Lactiplantibacillus plantarum supplementation could minimize the risk of the same. L. plantarum may confer beneficial effects in PM2.5-associated pulmonary inflammation due to significant antioxidant potential. We discussed L. plantarum's effect on PM2.5-induced reactive oxygen species (ROS), inflammatory cytokines, lipid peroxidation, and DNA damage. Available preclinical evidence shows L. plantarum induces gut-lung axis, SCFA, GABA, and other neurotransmitter signaling via gut microbiota modulation. SCFA signals are important in maintaining lung homeostasis and regulating intracellular defense mechanisms in alveolar cells. However, significant research is needed in this direction to contemplate L. plantarum's therapeutic potential in pulmonary allergies.
    Keywords:  Nrf2 activation; PM2.5-associated allergies; alveolar cell protection; anti-inflammatory cytokines; gut microbiota dysbiosis; gut-lung axis; probiotics supplementation; pulmonary inflammation
    DOI:  https://doi.org/10.3389/fcimb.2023.1290914
  61. Microorganisms. 2023 Dec 22. pii: 24. [Epub ahead of print]12(1):
    Microbiome in Cancer Development and Treatment.
    Sona Ciernikova, Aneta Sevcikova, Beata Mladosievicova, Michal Mego.
      Targeting the microbiome, microbiota-derived metabolites, and related pathways represents a significant challenge in oncology. Microbiome analyses have confirmed the negative impact of cancer treatment on gut homeostasis, resulting in acute dysbiosis and severe complications, including massive inflammatory immune response, mucosal barrier disruption, and bacterial translocation across the gut epithelium. Moreover, recent studies revealed the relationship between an imbalance in the gut microbiome and treatment-related toxicity. In this review, we provide current insights into the role of the microbiome in tumor development and the impact of gut and tumor microbiomes on chemo- and immunotherapy efficacy, as well as treatment-induced late effects, including cognitive impairment and cardiotoxicity. As discussed, microbiota modulation via probiotic supplementation and fecal microbiota transplantation represents a new trend in cancer patient care, aiming to increase bacterial diversity, alleviate acute and long-term treatment-induced toxicity, and improve the response to various treatment modalities. However, a more detailed understanding of the complex relationship between the microbiome and host can significantly contribute to integrating a microbiome-based approach into clinical practice. Determination of causal correlations might lead to the identification of clinically relevant diagnostic and prognostic microbial biomarkers. Notably, restoration of intestinal homeostasis could contribute to optimizing treatment efficacy and improving cancer patient outcomes.
    Keywords:  cancer treatment efficacy; cardiotoxicity; cognitive impairment; dysbiosis; fecal microbiota transplantation; late effects; probiotics; the gut microbiome
    DOI:  https://doi.org/10.3390/microorganisms12010024
  62. Methods Mol Biol. 2024 ;2766 247-261
    Macrophage Polarization and Osteoclast Differentiation.
    Noritaka Saeki, Akihiro Nakata.
      Macrophages are a key player to regulate rheumatoid arthritis pathogenesis from onset to remission. They can alter innate functions under microenvironmental conditions. To understand heterogeneous functions of macrophages in rheumatoid arthritis, several activated statuses of macrophages should be mimicked in vitro. Here, we describe basic protocols for macrophage polarization and osteoclast differentiation.
    Keywords:  Bone marrow-derived macrophages; Cellular metabolism; M1/M2 macrophages; Osteoclasts
    DOI:  https://doi.org/10.1007/978-1-0716-3682-4_26
  63. Virulence. 2024 Jan 22. 2306719
    Streptococcal arginine deiminase system defences macrophage bactericidal effect mediated by XRE family protein XtrSs.
    Yumin Zhang, Song Liang, Shidan Zhang, Qiankun Bai, Lei Dai, Jinxiu Wang, Huochun Yao, Wei Zhang, Guangjin Liu.
      The arginine deiminase system (ADS) has been identified in various bacteria and functions to supplement energy production and enhance biological adaptability. The current understanding of the regulatory mechanism of ADS and its effect on bacterial pathogenesis is still limited. Here, we found that the XRE family transcriptional regulator XtrSs negatively affected Streptococcus suis virulence and significantly repressed ADS transcription when the bacteria were incubated in blood. Electrophoretic mobility shift (EMSA) and lacZ fusion assays further showed that XtrSs directly bind the promoter of ArgR, an acknowledged positive regulator of bacterial ADS, to repress ArgR transcription. Moreover, we provided compelling evidence that S. suis could utilize arginine via ADS to adapt to acid stress, while ΔxtrSs enhanced this acid resistance by upregulating the ADS operon. Moreover, whole ADS-knockout S. suis increased arginine and antimicrobial NO in the infected macrophage cells, decreased intracellular survival, and even caused significant attenuation of bacterial virulence in a mouse infection model, while ΔxtrSs consistently presented the opposite results. Our experiments identified a novel ADS regulatory mechanism in S. suis, whereby XtrSs regulated ADS to modulate NO content in macrophages, promoting S. suis intracellular survival. Meanwhile, our findings provide a new perspective on how Streptococci evade the host's innate immune system.
    Keywords:  Streptococcus suis; acid stress; arginine deiminase system; nitric oxide; transcriptional regulation
    DOI:  https://doi.org/10.1080/21505594.2024.2306719
  64. Front Microbiol. 2023 ;14 1298570
    Probiotics in milk replacer affect the microbiome of the lung in neonatal dairy calves.
    Tara G McDaneld, Susan D Eicher, Aaron Dickey, Janice E Kritchevsky, Keith A Bryan, Carol G Chitko-McKown.
       Introduction: Probiotics have been investigated for their many health benefits and impact on the microbiota of the gut. Recent data have also supported a gut-lung axis regarding the bacterial populations (microbiomes) of the two locations; however, little research has been performed to determine the effects of oral probiotics on the microbiome of the bovine respiratory tract. We hypothesized that probiotic treatment would result in changes in the lung microbiome as measured in lung lavage fluid. Our overall goal was to characterize bacterial populations in the lungs of calves fed probiotics in milk replacer and dry rations from birth to weaning.
    Methods: A group of 20 dairy calves was split into two treatment groups: probiotic (TRT; N = 10, milk replacer +5 g/d probiotics; Bovamine Dairy, Chr. Hansen, Inc., Milwaukee, WI) and control (CON; N = 10, milk replacer only). On day 0, birth weight was obtained, and calves were provided colostrum as per the dairy SOP. On day 2, probiotics were added to the milk replacer of the treated group and then included in their dry ration. Lung lavages were performed on day 52 on five random calves selected from each treatment group. DNA was extracted from lavage fluid, and 16S ribosomal RNA (rRNA) gene hypervariable regions 1-3 were amplified by PCR and sequenced using next-generation sequencing (Illumina MiSeq) for the identification of the bacterial taxa present. Taxa were classified into both operational taxonomic units (OTUs) and amplicon sequence variants (ASVs).
    Results: Overall, the evaluation of these samples revealed that the bacterial genera identified in the lung lavage samples of probiotic-fed calves as compared to the control calves were significantly different based on the OTU dataset (p < 0.05) and approached significance for the ASV dataset (p < 0.06). Additionally, when comparing the diversity of taxa in lung lavage samples to nasal and tonsil samples, taxa diversity of lung samples was significantly lower (p < 0.05).
    Discussion: In conclusion, analysis of the respiratory microbiome in lung lavage samples after probiotic treatment provides insight into the distribution of bacterial populations in response to oral probiotics and demonstrates that oral probiotics affect more than the gut microbiome.
    Keywords:  16S rRNA; dairy cattle; lavage; microbiome; probiotic
    DOI:  https://doi.org/10.3389/fmicb.2023.1298570
  65. Front Immunol. 2023 ;14 1293048
    Lactobacillus rhamnosus ameliorates acne vulgaris in SD rats via changes in gut microbiota and associated tryptophan metabolism.
    Yukun Huang, Yaxin Huang, Dengmei Xia, Lu Liu, Xia Xiong, Yongliang Ouyang, Yongqiong Deng.
       Background: The depletion of beneficial bacteria in the gut has been found in patients with acne vulgaris, and in previous studies, the supplement of Lactobacillus rhamnosus led to the improvement of adult acne. Nevertheless, the potential mechanism of L. rhamnosus in the amelioration of acne vulgaris has not been elucidated yet.
    Methods: To mimic the human intestinal environment, a pseudo-germ-free rat model was used, and then gut microbiota from healthy individuals and acne patients were transplanted into rats. The effects of L. rhamnosus and tryptophan (Trp) metabolites on a rat acne model were investigated by gavage. Then, 16S rRNA analysis and targeted measurement of metabolites were performed to discover the differences in gut microbiota and metabolites between groups. Finally, HaCaT cells pretreated with Cutibacterium acnes were employed to validate the effect and mechanism of Trp metabolites on acne.
    Results: L. rhamnosus significantly improved acne-like symptoms in rats by suppressing the level of inflammatory cytokines such as IL-1β, IL-6, and TNF-α. L. rhamnosus induced an increase in the production of indole-3-acetic acid (IAA) and indole via targeted Trp metabolic analyses. Furthermore, L. rhamnosus promoted bacterial diversity and also enhanced the Firmicutes/Bacteroidota (F/B) ratio, which was positively related to both IAA and indole. Finally, the roles of IAA and indole in alleviating acne vulgaris were confirmed both in vitro and in vivo, which could be reversed by AhR inhibitors.
    Conclusion: Our study demonstrated that L. rhamnosus could exert its therapeutic effects on acne vulgaris by modulating the gut microbiota and regulating associated Trp metabolites.
    Keywords:  Lactobacillus rhamnosus; acne vulgaris; aryl hydrocarbon receptor; gut microbiota; tryptophan
    DOI:  https://doi.org/10.3389/fimmu.2023.1293048
  66. Cell Commun Signal. 2024 Jan 26. 22(1): 74
    Macrophage barrier in the tumor microenvironment and potential clinical applications.
    Shuai Ji, Yuqing Shi, Bo Yin.
      The tumor microenvironment (TME) constitutes a complex microenvironment comprising a diverse array of immune cells and stromal components. Within this intricate context, tumor-associated macrophages (TAMs) exhibit notable spatial heterogeneity. This heterogeneity contributes to various facets of tumor behavior, including immune response modulation, angiogenesis, tissue remodeling, and metastatic potential. This review summarizes the spatial distribution of macrophages in both the physiological environment and the TME. Moreover, this paper explores the intricate interactions between TAMs and diverse immune cell populations (T cells, dendritic cells, neutrophils, natural killer cells, and other immune cells) within the TME. These bidirectional exchanges form a complex network of immune interactions that influence tumor immune surveillance and evasion strategies. Investigating TAM heterogeneity and its intricate interactions with different immune cell populations offers potential avenues for therapeutic interventions. Additionally, this paper discusses therapeutic strategies targeting macrophages, aiming to uncover novel approaches for immunotherapy. Video Abstract.
    Keywords:  Macrophage; Tumor immunology; Tumor microenvironment; Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1186/s12964-023-01424-6
  67. Am J Clin Dermatol. 2024 Jan 22.
    The Skin Microbiome and its Significance for Dermatologists.
    Cleo Whiting, Sara Abdel Azim, Adam Friedman.
      The skin is a physical and immunological barrier to the external environment. Its large surface area is colonized by diverse communities of microorganisms, including bacteria, viruses, fungi, and Demodex species mites. These microorganisms and their genetic material together create the skin microbiome. Physiologic and anatomic properties of skin sites create biogeographical habitats (dry, moist, and sebaceous) where distinct microbiota communities reside. Although, in general, the composition of these habitats is maintained from person to person, the skin microbiome of an individual also has unique microbial features. Dysbiosis occurs when the normal abundance, composition, or location of the microbiota is changed, most notably there is a decrease in flora diversity. Certain skin diseases, including atopic dermatitis, rosacea, and psoriasis are associated with cutaneous dysbiosis, and even disruption of the gut microbiota. Studies have shown that current treatments for these dermatologic conditions can alter/stabilize the skin microbiome, and there is emerging research detailing the impact of prebiotics, probiotics, and postbiotics on these conditions. Although clinical guidelines do not currently exist, clinical studies support the safety and possible benefits of using topical prebiotics and postbiotics and oral probiotics for a variety of skin conditions. Until such guidelines exist, utilizing carefully designed clinical studies to inform clinical practice is recommended.
    DOI:  https://doi.org/10.1007/s40257-023-00842-z
  68. Nutrients. 2024 Jan 17. pii: 272. [Epub ahead of print]16(2):
    From Birth to Weaning: A Window of Opportunity for Microbiota.
    Valentina Biagioli, Greta Volpedo, Antonella Riva, Paolo Mainardi, Pasquale Striano.
      (1) Background: The first 1000 days of life constitute a critical window of opportunity for microbiota development. Nutrients play a crucial role in enriching and diversifying the microbiota, derived not only from solid food but also from maternal dietary patterns during gestation. (2) Methods: We conducted a comprehensive literature review using the PubMed database, covering eleven years (2013-2023). We included English-language reviews, original research papers, and meta-analyses, while excluding case reports and letters. (3) Results: Consensus in the literature emphasizes that our interaction with a multitude of microorganisms begins in the intrauterine environment and continues throughout our lives. The existing data suggest that early nutritional education programs, initiated during pregnancy and guiding infant diets during development, may influence the shaping of the gut microbiota, promoting long-term health. (4) Conclusions: Further research is necessary in the coming years to assess potential interventions and early nutritional models aimed at modulating the pediatric microbiota, especially in vulnerable populations such as premature newborns.
    Keywords:  complementary feeding; gut–brain axis; human milk oligosaccharides; microbiota; weaning
    DOI:  https://doi.org/10.3390/nu16020272
  69. Pathogens. 2024 Jan 15. pii: 76. [Epub ahead of print]13(1):
    Biofilm Producing Methicillin-Resistant Staphylococcus aureus (MRSA) Infections in Humans: Clinical Implications and Management.
    Ashlesha Kaushik, Helen Kest, Mangla Sood, Bryan W Steussy, Corey Thieman, Sandeep Gupta.
      Since its initial description in the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has developed multiple mechanisms for antimicrobial resistance and evading the immune system, including biofilm production. MRSA is now a widespread pathogen, causing a spectrum of infections ranging from superficial skin issues to severe conditions like osteoarticular infections and endocarditis, leading to high morbidity and mortality. Biofilm production is a key aspect of MRSA's ability to invade, spread, and resist antimicrobial treatments. Environmental factors, such as suboptimal antibiotics, pH, temperature, and tissue oxygen levels, enhance biofilm formation. Biofilms are intricate bacterial structures with dense organisms embedded in polysaccharides, promoting their resilience. The process involves stages of attachment, expansion, maturation, and eventually disassembly or dispersion. MRSA's biofilm formation has a complex molecular foundation, involving genes like icaADBC, fnbA, fnbB, clfA, clfB, atl, agr, sarA, sarZ, sigB, sarX, psm, icaR, and srtA. Recognizing pivotal genes for biofilm formation has led to potential therapeutic strategies targeting elemental and enzymatic properties to combat MRSA biofilms. This review provides a practical approach for healthcare practitioners, addressing biofilm pathogenesis, disease spectrum, and management guidelines, including advances in treatment. Effective management involves appropriate antimicrobial therapy, surgical interventions, foreign body removal, and robust infection control practices to curtail spread within healthcare environments.
    Keywords:  MRSA; antibiotics; biofilm; infection; methicillin-resistant Staphylococcus aureus; treatment
    DOI:  https://doi.org/10.3390/pathogens13010076
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