bims-bac4me 2024-12-15 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–12–15
thirty papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Induction of Innate Immune Memory in LPS-Primed Microglial Cells by Water-Soluble Chitosan.
Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.
Neuraminidase-mediated enhancement of Streptococcus pneumoniae colonization is associated with altered mucus characteristics and distribution.
Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3.
Monocyte-Derived Macrophages Induce Alveolar Macrophages Death via TNF-α in Acute Lung Injury.
Discovery and engineering of the antibody response to a prominent skin commensal.
Evaluating the effects of ivacaftor exposure on Staphylococcus aureus small colony variant development and antibiotic tolerance.
Interplay of niche and respiratory network in shaping bacterial colonization.
The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children.
Regulatory dynamics of arginine metabolism in Staphylococcus aureus.
Streptococcus pneumoniae GAPN is a key metabolic player necessary for host infection.
Selenoproteome depletion enhances oxidative stress and alters neutrophil functions in Citrobacter rodentium infection leading to gastrointestinal inflammation.
Skin autonomous antibody production regulates host-microbiota interactions.
Linking innate immune evasion to pandemic potential.
Porphyromonas gingivalis-Lipopolysaccharide Induced Gingival Fibroblasts Trained Immunity Sustains Inflammation in Periodontitis.
Extracellular Hsp70 Is Involved in the CXCL12/CXCR4 Pathway in Primary Human Nasal Epithelial Cells: A Preliminary Study.
Broadly Accessible 3D In Vitro Skin Model as a Comprehensive Platform for Antibacterial Therapy Screening.
Metabolic reprogramming, sensing, and cancer therapy.
M2 macrophage derived HMOX1 defines chronic rhinosinusitis with nasal polyps.
Nutrient-driven histone code determines exhausted CD8+ T cell fates.
Decoding bacterial communication: Intracellular signal transduction, quorum sensing, and cross-kingdom interactions.
Screening of lactic acid bacteria from the milk of Sahiwal cows and characterization of their probiotic potential for preventing bovine mastitis.
M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells.
Palmitoleic acid sensitizes vancomycin-resistant Staphylococcus aureus to vancomycin by outpacing the expression of resistance genes.
Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.
Candida albicans enhances Staphylococcus aureus virulence by progressive generation of new phenotypes.
Antibiotic-perturbed microbiota and the role of probiotics.
When Can a MRSA Nares Swab Guide Antibiotic Stewardship?: What the Nose Knows.
AKRs confer oligodendrocytes resistance to differentiation-stimulated ferroptosis.
BCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases.

Biomed Res Int. 2024 ;2024 8027006

Induction of Innate Immune Memory in LPS-Primed Microglial Cells by Water-Soluble Chitosan.

Vo Thuy Anh Thu, Thi Xoan Hoang, Jae Kweon Park, Jae Young Kim.

  Innate immune memory or trained immunity refers to a long-lasting response of the innate immune cells against repeated exposure to the homogenous or heterogenous infectious agent. The trained immunity is induced through epigenetic modification and is characterized by the change of both intracellular immunological signaling and cellular metabolism. Recently, different groups have tried to establish protocols to generate trained innate immune cells. However, the molecular basis of innate memory induction remains poorly understood. Here, we evaluated the impact of water-soluble chitosan on the innate immune memory induction in microglial cells primed with LPS. The trained-immune response was accessed by measuring proinflammatory markers, metabolic change, and epigenetic modification. We showed that the stimulation/restimulation with LPS only caused a robust reduction of iNOS, and proinflammatory cytokines, indicating induced immune tolerance. In contrast, the treatment of chitosan induces long-lasting memory microglial cells accompanied by a high level of iNOS, increased lactate production, induced epigenetic modification, and the upregulation of proinflammatory cytokines upon further exposure to the same stimulus. These findings suggest that chitosan induces microglial-trained immunity by targeting distinct epigenetic and metabolic pathways; therefore, chitosan treatment may provide a novel approach for targeting innate immunity towards a memory-like response in an in vitro model.

Keywords:  microglia; trained immunity; water-soluble chitosan

DOI:  https://doi.org/10.1155/bmri/8027006
Infect Immun. 2024 Dec 10. e0047224

Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.

Aayush Bahl, Saurabh Pandey, Roopshali Rakshit, Sashi Kant, Deeksha Tripathi.

  In contrast to adaptive immunity, which relies on memory T and B cells for long-term pathogen-specific responses, trained immunity involves the enhancement of innate immune responses through cellular reprogramming. Experimental evidence from animal models and human studies supports the concept of trained immunity and its potential therapeutic applications in the development of personalized medicine. However, there remains a huge gap in understanding the mechanisms, identifying specific microbial triggers responsible for the induction of trained immunity. This underscores the importance of investigating the potential role of trained immunity in redefining host defense and highlights future research directions. This minireview will provide a comprehensive summary of the new paradigm of trained immunity or innate memory pathways. It will shed light on infection-induced pathways through non-specific stimulation within macrophages and natural killer cells, which will be further elaborated in multiple disease perspectives caused by infectious agents such as bacteria, fungi, and viruses. The article further elaborates on the biochemical and cellular basis of trained immunity and its impact on disease status during recurrent exposures. The review concludes with a perspective segment discussing potential therapeutic benefits, limitations, and future challenges in this area of study. The review also sheds light upon potential risks involved in the induction of trained immunity.

Keywords:  adaptive immunity; epigenetic reprogramming; infection; innate immunity; microbial triggers; trained immunity

DOI:  https://doi.org/10.1128/iai.00472-24
mBio. 2024 Dec 11. e0257924

Neuraminidase-mediated enhancement of Streptococcus pneumoniae colonization is associated with altered mucus characteristics and distribution.

Matthew T Montgomery, Mila Ortigoza, Cynthia Loomis, Jeffrey N Weiser.

  Upon entry into the upper respiratory tract (URT), Streptococcus pneumoniae (Spn) upregulates neuraminidases (NA) that cleave sialic acid (SA) from host glycans. Because sialylation is thought to contribute to the physical properties that determine mucus function, we posited that Spn directly alters host mucus through NA activity. By directly imaging the colonized URT, we demonstrated NA-mediated alterations to the characteristics and distribution of mucus along the respiratory epithelium, where colonizing bacteria are found. Mucus exposed to NA showed increased localization within goblet cells and lining the glycocalyx. By contrast, NA-naïve mucus was more likely to be observed sloughing away from the epithelial surface. We also visualized Spn in the URT and observed that NA promoted efficient bacterial localization to the firm mucus layer overlying the glycocalyx, whereas NA-deficient Spn was associated more with loose mucus. By facilitating tighter association with the glycocalyx, NA promoted increased Spn colonization density. The magnitude of the NA-mediated effect on colonization was widened during late colonization by increased evasion of host-mediated clearance mechanisms. Thus, Spn-encoded NAs directly modify the host environment by desialylating mucus, which allows close interaction with mucus at the epithelium, and this is associated with enhanced bacterial colonization.
IMPORTANCE: Although severe illness and death caused by Spn result from secondary invasive diseases including pneumonia, sepsis, and meningitis, stable colonization of the upper respiratory tract (URT) is a prerequisite to invasive disease. Therefore, understanding host-Spn dynamics during asymptomatic colonization of the URT is warranted with respect to the pathogenesis of Spn disease. In this study, we found that Spn NA activity directly alters mucus characteristics that result in increased density and duration of URT colonization. Therefore, targeting Spn NA activity during URT colonization may be a viable strategy to mitigate Spn infection.

Keywords:  Streptococcus pneumoniae; colonization; mucus; neuraminidase; upper respiratory tract

DOI:  https://doi.org/10.1128/mbio.02579-24
Blood. 2024 Dec 10. pii: blood.2023023417. [Epub ahead of print]

Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3.

Oriana Marques, Natalie K Horvat, Laura Zechner, Silvia Colucci, Richard Sparla, Stefan Zimmermann, Christopher J Neufeldt, Sandro Altamura, Ruiyue Qiu, Katja Müdder, Günter Weiss, Matthias W Hentze, Martina U Muckenthaler.

Anemia of Inflammation is a prevalent co-morbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting Ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. While the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 mRNA expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signalling regulators of Slc40a1 mRNA repression downstream of TLRs and NFкB signaling. Interestingly, the NFкB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand LPS, the cytokine TNFβ/LTA and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the Histone deacetylases (HDAC) 1 and 3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pre-treatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NFкB to repress Slc40a1 transcription. Consistently, recruitment of HDAC 1 and 3 to the Slc40a1 ARE following stimulation with heat-killed Staphylococcus aureus is dependent on NFκB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.

DOI: https://doi.org/10.1182/blood.2023023417
Immun Inflamm Dis. 2024 Dec;12(12): e70081

Monocyte-Derived Macrophages Induce Alveolar Macrophages Death via TNF-α in Acute Lung Injury.

Junjie Xiao, Fei Hou, Huan Wang, Ruixuan Wang, Ying Liu, Xiayan Wu, Lixin Xie.

   INTRODUCTION: Acute lung injury (ALI) and its subsequent progression to acute respiratory distress syndrome (ARDS) are severe respiratory conditions. They are marked by rapid lung function deterioration and extensive pulmonary inflammation, often resulting in critical patient outcomes. Alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs) are two distinct subsets of lung macrophages present in the alveoli during ALI. Both are critical mediators of pulmonary inflammation. Our study examined the interplay between AMs and MDMs in the inflammatory environment of ALI/ARDS.
METHODS: Mice were treated with lipopolysaccharide (LPS) to establish ALI models. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of tissue damage. In vivo, CCR2-deficient mice or depleting peripheral blood mononuclear cells by clodronate liposomes were used to reduce MDMs recruitment. The bronchoalveolar lavage fluid (BALF) supernatants were used for cytokine and total protein analyses. AMs and MDMs in the BALF were analyzed by flow cytometry. The levels of AMs death were determined through propidium iodide staining and measured by flow cytometry. In vitro, primary AMs were exposed to MDM-conditioned medium or TNF-α, and their death levels were assessed under a fluorescence microscope with propidium iodide staining.
RESULTS: AMs significantly decrease in number and undergo extensive cell death during ALI. The reduced MDMs recruitment can increase the number of AMs, reduce AMs death, and alleviate lung injury. In vitro, MDM-conditioned medium can induce AMs death and TNF-α is one of the major secretions. It indicates that TNF-α stimulation in vitro promotes AMs death. In vivo, MDMs are identified as the primary cells secreting TNF-α. Additionally, the treatment with TNF-α antagonists can reduce AMs death and the severity of lung injury.
CONCLUSION: Our study demonstrates that MDMs contribute to AMs death during ALI through TNF-α. Targeting TNF-α may offer a therapeutic strategy to mitigate AMs death and lung injury in ALI/ARDS.

Keywords:  TNF‐α; acute lung injury; alveolar macrophages; cell death; monocyte‐derived macrophages

DOI:  https://doi.org/10.1002/iid3.70081
Nature. 2024 Dec 11.

Discovery and engineering of the antibody response to a prominent skin commensal.

Djenet Bousbaine, Katherine D Bauman, Y Erin Chen, Pranav V Lalgudi, Tam T D Nguyen, Joyce M Swenson, Victor K Yu, Eunice Tsang, Sean Conlan, David B Li, Amina Jbara, Aishan Zhao, Arash Naziripour, Alessandra Veinbachs, Yu E Lee, Jennie L Phung, Alex Dimas, Sunit Jain, Xiandong Meng, Thi Phuong Thao Pham, Martin I McLaughlin, Layla J Barkal, Inta Gribonika, Koen K A Van Rompay, Heidi H Kong, Julie A Segre, Yasmine Belkaid, Christopher O Barnes, Michael A Fischbach.

The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection1. However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high antibody titers under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination.

DOI: https://doi.org/10.1038/s41586-024-08489-4
JAC Antimicrob Resist. 2024 Dec;6(6): dlae185

Evaluating the effects of ivacaftor exposure on Staphylococcus aureus small colony variant development and antibiotic tolerance.

Gretchen E Bollar, Kendall M Shaffer, Johnathan D Keith, Ashley M Oden, Alexander E Dowell, Kevin J Ryan, Edward P Acosta, Jennifer S Guimbellot, Megan R Kiedrowski, Susan E Birket.

Background: Ivacaftor exhibits anti-staphylococcal properties but does not clear Staphylococcus aureus from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow S. aureus to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.
Methods: Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of S. aureus during ivacaftor treatment was assessed in an hG551D rat model of lung infection. S. aureus adaptation to therapeutic concentrations of ivacaftor was investigated in vitro by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays.
Results: Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During S. aureus infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of S. aureus to ivacaftor in vitro led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance.
Conclusions: Treatment with ivacaftor did not alter S. aureus burden in the cystic fibrosis rat and led to the formation of tolerant SCVs in vitro, suggesting that development of an SCV phenotype may allow S. aureus to persist in the cystic fibrosis lung during ivacaftor therapy.

DOI: https://doi.org/10.1093/jacamr/dlae185
J Biol Chem. 2024 Dec 09. pii: S0021-9258(24)02554-7. [Epub ahead of print] 108052

Interplay of niche and respiratory network in shaping bacterial colonization.

Stuti Srivastav, Arpita Biswas, Amitesh Anand.

  The human body is an intricate ensemble of prokaryotic and eukaryotic cells, and this coexistence relies on the interplay of many biotic and abiotic factors. The inhabiting microbial population has to maintain its physiological homeostasis under highly dynamic and often hostile host environments. While bacterial colonization primarily relies on the metabolic suitability for the niche, there are reports of active remodeling of niche microenvironments to create favorable habitats, especially in the context of pathogenic settlement. Such physiological plasticity requires a robust metabolic system, often dependent on an adaptable energy metabolism. This review focuses on the respiratory electron transport system and its adaptive consequences within the host environment. We provide an overview of respiratory chain plasticity, which allows pathogenic bacteria to niche-specify, niche-diversify, mitigate inflammatory stress, and outcompete the resident microbiota. We have reviewed existing and emerging knowledge about the role of respiratory chain components responsible for the entry and exit of electrons in influencing the pathogenic outcomes.

Keywords:  Bacterial pathogenesis; bacterial metabolism; bioenergetics; metabolic plasticity; respiratory chain

DOI:  https://doi.org/10.1016/j.jbc.2024.108052
Cell Rep Med. 2024 Nov 29. pii: S2666-3791(24)00607-4. [Epub ahead of print] 101836

The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children.

REspiratory Syncytial virus Consortium in EUrope (RESCEU) investigators

  Respiratory syncytial virus (RSV) is the leading cause of infant respiratory infections and hospitalizations. To investigate the relationship between the respiratory microbiome and RSV infection, we sequence nasopharyngeal samples from a birth cohort and a pediatric case-control study (Respiratory Syncytial virus Consortium in Europe [RESCEU]). 1,537 samples are collected shortly after birth ("baseline"), during RSV infection and convalescence, and from healthy controls. We find a modest association between baseline microbiota and the severity of consecutive RSV infections. The respiratory microbiota during infection clearly differs between infants with RSV and controls. Haemophilus, Streptococcus, and Moraxella abundance are associated with severe disease and persistence of symptoms, whereas stepwise increasing abundance of Dolosigranulum and Corynebacterium is associated with milder disease and health. We conclude that the neonatal respiratory microbiota is only modestly associated with RSV severity during the first year of life. However, the respiratory microbiota at the time of infection is strongly associated with disease severity and residual symptoms.

Keywords:  16S; RSV; airway; birth cohort; case-control; microbiota; nasopharynx; respiratory; severity

DOI:  https://doi.org/10.1016/j.xcrm.2024.101836
Biochem Soc Trans. 2024 Dec 10. pii: BST20240710. [Epub ahead of print]

Regulatory dynamics of arginine metabolism in Staphylococcus aureus.

Itidal Reslane, Gabrielle F Watson, Luke D Handke, Paul D Fey.

  Staphylococcus aureus is a highly significant pathogen with several well studied and defined virulence factors. However, the metabolic pathways that are required to facilitate infection are not well described. Previous data have documented that S. aureus requires glucose catabolism during initial stages of infection. Therefore, certain nutrients whose biosynthetic pathway is under carbon catabolite repression and CcpA, including arginine, must be acquired from the host. However, even though S. aureus encodes pathways to synthesize arginine, biosynthesis of arginine is repressed even in the absence of glucose. Why is S. aureus a functional arginine auxotroph? This review discusses recently described regulatory mechanisms that are linked to repression of arginine biosynthesis using either proline or glutamate as substrates. In addition, recent studies are discussed that shed insight into the ultimate mechanisms linking arginine auxotrophy and infection persistence.

Keywords:   Staphylococcus aureus ; amino acids; arginine; auxotrophy; metabolism

DOI:  https://doi.org/10.1042/BST20240710
Protein Sci. 2025 Jan;34(1): e5253

Streptococcus pneumoniae GAPN is a key metabolic player necessary for host infection.

Eunjeong Lee, Anthony Saviola, Shaun Bevers, Jasmina S Redzic, Sean P Maroney, Steven Shaw, Emily Tamkin, Sam Fulte, Travis Nemkov, Nancy Meyer, Angelo D'Alessandro, Kirk C Hansen, Sarah E Clark, Elan Eisenmesser.

  Streptococcus pneumoniae (S. pneumoniae) employs various metabolic pathways to generate nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for redox balance, fatty acid synthesis, and energy production. GAPN, a non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, plays a role in this process by directly reducing NADP+ to NADPH, effectively contributing to glucose metabolism. However, its relative importance for S. pneumoniae metabolism and infection has remained unknown. Here, we performed a comprehensive characterization of S. pneumoniae GAPN through kinetic assays, isothermal titration calorimetry (ITC), cryo-EM, mass spectrometry, and infection assays. Despite its structural similarities to its homologues in other species, S. pneumoniae GAPN exhibits negative cooperativity with respect to its substrate, glyceraldehyde-3-phosphate (G3P), suggesting a unique regulatory mechanism. Our results demonstrate that GAPN knockout leads to significant metabolic reprogramming, including increased glycogen storage that leads to enhanced fatty acid metabolism. This collectively reduces the ability of S. pneumoniae to manage oxidative stress and sustain infection. Our findings highlight GAPN as a critical enzyme for S. pneumoniae metabolic balance and suggest that its inhibition could serve as a potential strategy for therapeutic intervention in pneumococcal diseases.

Keywords:  GAPN; cryo‐EM; glycolysis; metabolism; structure

DOI:  https://doi.org/10.1002/pro.5253
Free Radic Biol Med. 2024 Dec 09. pii: S0891-5849(24)01129-8. [Epub ahead of print]

Selenoproteome depletion enhances oxidative stress and alters neutrophil functions in Citrobacter rodentium infection leading to gastrointestinal inflammation.

Tai-Jung Lee, Hsiao-Chi Liao, Agus Salim, Shaneice K Nettleford, Kendall L Kleinman, Bradley A Carlson, K Sandeep Prabhu.

  Reactive oxygen species (ROS) play a critical role in modulating a range of proinflammatory functions in neutrophils, as well as regulating neutrophil apoptosis and facilitating the resolution of an inflammatory response. Selenoproteins with the 21st amino acid, selenocysteine (Sec), regulate the immune mechanisms through the modulation of the redox homeostasis aiding in the efficient resolution of inflammation, while their role in neutrophil functions during diseases remains unclear. To study the role of selenoproteins in neutrophils during infection, we challenged the granulocyte-specific tRNASec (Trsp) knockout mice (TrspN) with Citrobacter rodentium (C. rodentium), a murine pathogenic bacterium. Reduced bacterial shedding during the disease-clearing phase and increased tissue damage and neutrophil accumulation in the colon of the TrspN mice were observed following infection. TrspN neutrophils showed increased intracellular ROS accumulation during ex vivo C. rodentium stimulation and upregulated fMLP-induced chemotaxis. We also observed delayed neutrophil apoptosis, reduced efferocytosis of TrspN neutrophils, and increased abundance of apoptotic cells in the colon of TrspN mice. Together, these studies indicate that selenoprotein depletion results in increased neutrophil migration to the gut accompanied by ROS accumulation, while downregulating neutrophil apoptosis and subsequent efferocytosis by macrophages. Such an increase in inflammation followed by impaired resolution culminates in decreased bacterial load but with exacerbated host tissue damage.

Keywords:  Apoptosis; Efferocytosis; Migration; Reactive Oxygen Species; Resolution

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.025
Nature. 2024 Dec 11.

Skin autonomous antibody production regulates host-microbiota interactions.

Inta Gribonika, Victor I Band, Liang Chi, Paula Juliana Perez-Chaparro, Verena M Link, Eduard Ansaldo, Cihan Oguz, Djenet Bousbaine, Michael A Fischbach, Yasmine Belkaid.

The microbiota colonizes each barrier site and broadly controls host physiology1. However, when uncontrolled, microbial colonists can also promote inflammation and induce systemic infection2. The unique strategies employed at each barrier tissue to control the coexistence of the host with its microbiota remain largely elusive. Here we uncover that, within the skin, host-microbiota symbiosis depends on the remarkable ability of the skin to act as an autonomous lymphoid organ. Notably, an encounter with a new skin commensal promotes two parallel responses, both under the control of Langerhans cells. On one hand, skin commensals induce the formation of classical germinal centers within the lymph node associated with IgG1 and IgG3 antibody responses. On the other hand, microbial colonization also leads to the development of tertiary lymphoid organs within the skin that can locally sustain IgG2b and IgG2c responses. These phenomena are supported by the ability of regulatory T cells to convert into T follicular helper cells. Skin autonomous production of antibodies is sufficient to control local microbial biomass, as well as subsequent systemic infection with the same microbe. Collectively, these results reveal a striking compartmentalization of humoral responses to the microbiota allowing for control of both microbial symbiosis and potential pathogenesis.

DOI: https://doi.org/10.1038/s41586-024-08376-y
Nat Rev Microbiol. 2024 Dec 11.

Linking innate immune evasion to pandemic potential.

Lucy G Thorne.

DOI: https://doi.org/10.1038/s41579-024-01137-8
J Periodontal Res. 2024 Dec 12.

Porphyromonas gingivalis-Lipopolysaccharide Induced Gingival Fibroblasts Trained Immunity Sustains Inflammation in Periodontitis.

Jiayi Liu, Haoyang Tian, Jinhong Ju, Fujiao Nie, Qiuyue Yin, Jingjing Zhao, Suli Wang, Hongmei Guo, Pishan Yang.

   AIM: To investigate whether trained immunity occurs in gingival fibroblasts (GFs) and its relationship to the persistence of inflammation in periodontitis.
METHODS: Periodontally healthy and inflammatory gingival fibroblasts (HGFs and IGFs) were cultured through continuous adherence subculture of tissue blocks. Trained immunity in HGFs was evaluated via a classic in vitro model, with relevant markers assessed via enzyme-linked immunosorbent assay, lactate content assay, glycolytic rate assay, and chromatin immunoprecipitation. A histone methyltransferase blocker and a PI3K inhibitor were added to investigate the mechanisms underlying trained immunity. The relationship between trained immunity and periodontitis was further examined via immunofluorescence staining and chromatin immunoprecipitation on IGFs.
RESULTS: Compared with untrained cells, GFs trained with Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) exhibited a significant increase in IL-6 and TNF-α secretion, enhanced glycolytic metabolism, and enriched mono-methylation of lysine 4 on histone H3 (H3K4me1) at the enhancer regions of TNF-α and IL-6. The addition of a histone methyltransferase blocker and a PI3K inhibitor greatly reduced trained immunity. Additionally, the response of IGFs to P. gingivalis-LPS stimulation and their epigenetic modifications were similar to those observed in trained HGFs.
CONCLUSION: This study novelly discovered that both P. gingivalis-LPS-stimulated HGFs and IGFs in periodontitis acquired trained immunity. Following P. gingivalis-LPS stimulation, HGFs underwent metabolic and epigenetic changes via the PI3K/AKT pathway, with these epigenetic changes also observed in IGFs. This finding suggests that trained immunity in GFs may be a key mechanism underlying the recurrence and persistence of periodontitis.

Keywords:  PI3K/AKT pathway; gingival fibroblast; inflammation; metabolic and epigenetic reprogramming; trained immunity

DOI:  https://doi.org/10.1111/jre.13372
J Rhinol. 2023 Nov;30(3): 135-138

Extracellular Hsp70 Is Involved in the CXCL12/CXCR4 Pathway in Primary Human Nasal Epithelial Cells: A Preliminary Study.

Seong Hee Kim, Dong Young Kahng, Kyung Soo Kim, Hyun Jin Min.

   Background and Objectives: To date, no studies have been conducted on the interaction between extracellular heat shock protein 70 (Hsp70) and C-X-C chemokine receptor type 4 (CXCR4) in the upper airway. We aimed to evaluate the relationship between extracellular Hsp70 and CXCR4 and their role in the primary human nasal epithelium.
Methods: We cultured primary human nasal epithelial (HNE) cells in an air-liquid interface. Macrogen performed single-cell quantitative polymerase chain reaction and sequencing. We conducted western blot analysis for the CXCR4 and mitogen-activated protein kinase (MAPK) pathways.
Results: Extracellular Hsp70 treatment significantly increased the genetic expression and protein levels of CXCR4 in primary HNE cells. Phospho-ERK expression was increased by cotreatment with Hsp70 and CXCL12, but inhibited by pretreatment with AMD3100, a CXCR4 inhibitor. Pretreatment with an anti-Hsp70 antibody reduced phospho-ERK expression upregulation induced by cotreatment with Hsp70 and CXCL12.
Conclusion: Extracellular Hsp70 participates in the activation of the CXCR4-dependent downstream signaling pathway in HNE cells. Further studies should evaluate the extracellular Hsp70-CXCL12/CXCR4 axis and the role of its components in the development of inflammatory diseases.

Keywords:  CXCL12; CXCR4; Hsp70; Nasal epithelium

DOI:  https://doi.org/10.18787/jr.2023.00042
ACS Appl Mater Interfaces. 2024 Dec 12.

Broadly Accessible 3D In Vitro Skin Model as a Comprehensive Platform for Antibacterial Therapy Screening.

Simona Villata, Désirée Baruffaldi, Raquel Cue Lopez, Camilla Paoletti, Paula Bosch, Lucia Napione, Andrea M Giovannozzi, Candido Fabrizio Pirri, Enrique Martinez-Campos, Francesca Frascella.

  Skin infections are currently a worldwide emergency as antibiotic-resistant bacteria are spreading, leading to the ineffectiveness of most antibiotics and antibacterial strategies. Consequently, there is an urgency of developing and testing innovative antibacterial therapies. As traditional 2D cell culture and planktonic bacteria culture can be obsolete due to their incapability of resembling the complex infection environment, 3D in vitro skin models can be a powerful tool to test and validate therapies. In this article, a 3D in vitro epidermis-dermis skin model has been developed and biofabricated to be broadly available, reaching a balance between the simplicity and reproducibility of the model and its complexity in terms of wound, infection, and treatment response. The results are really promising, as the skin model developed a comprehensive physical barrier. To further investigate the skin model, controlled wounding, infection, and antibiotic treatments were performed. The results were remarkable: Not only was the unwounded epidermal barrier able to partially stop the bacterial proliferation, but the entire system reacted to both wound and infection in a complex and complete way. Extracellular matrix deposition and remodeling, inflammatory response, antimicrobial peptide production, and change in cellular behaviors, from epithelial to mesenchymal and from fibroblasts to myofibroblasts, were witnessed, with different extents depending on the bacterial strain. In addition, the inflammatory response to the antibiotic administration was opposite for the two bacterial infections, probably revealing the release of inflammatory endotoxins during Escherichia coli death. In conclusion, the presented 3D in vitro skin model has all the characteristics to be a future landmark as a platform for antibacterial strategy therapy testing.

Keywords:  3D in vitro skin model; bacterial infection; barrier effect; immune response; therapy testing; wound healing

DOI:  https://doi.org/10.1021/acsami.4c16397
Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064

Metabolic reprogramming, sensing, and cancer therapy.

Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.

  The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy

DOI:  https://doi.org/10.1016/j.celrep.2024.115064
Clin Transl Allergy. 2024 Dec;14(12): e70014

M2 macrophage derived HMOX1 defines chronic rhinosinusitis with nasal polyps.

Enhao Wang, Yanghe Hao, Jing Song, Jing Yuan, Yu Hong, Ying Li, Yang Wang, Chengshuo Wang, Ming Wang, Luo Zhang.

   BACKGROUND: Molecular signatures of chronic rhinosinusitis with nasal polyps (CRSwNP) related to macrophages remain unclear. This study aimed to develop a macrophage-associated diagnostic signature for CRSwNP.
METHODS: Transcriptome data from 54 patients with CRSwNP and 37 healthy controls across GSE136825, GSE36830, and GSE72713 were used to identify differentially expressed genes (DEGs) between two groups. Gene Set Enrichment Analysis and Weighted Gene Co-Expression Network Analysis pinpointed crucial pathways and gene clusters. A diagnostic model was created from these analyses and receiver operating characteristic curve (ROC), and further validated in our transcriptome data from 29 samples. Immune cell infiltration analysis was performed and linked those diagnostic genes to macrophages and verified by single-cell RNA sequencing data. Immunofluorescence co-staining of CD163 and HMOX1 was performed in nasal tissues. Mouse bone marrow-derived macrophage (BMDMs) cultures were used in functional experiments. Correlations between the expression of HMOX1 and eotaxin genes were investigated.
RESULTS: DEGs of CRSwNP versus control group were enriched in the INTERLEUKIN_4_AND_13_SIGNALING pathways. A four-gene diagnostic model (HMOX1, ALOX5, F13A1 and ITGB2) was developed and demonstrated high diagnostic precision with an area under ROC curve of 0.980 for training dataset and 0.895 for test dataset. M2 macrophage presence and HMOX1 expression significantly correlated with CRSwNP (p < 0.001). Single-cell RNA sequencing data underscored the altered cellular composition in CRSwNP, with HMOX1 notably expressed in M2 macrophages. Immunofluorescence staining highlighted the increased infiltration of CD163+ M2 macrophages in nasal mucosa samples of eosinophilic CRSwNP, which correlated with HMOX1 protein levels (p < 0.05). The HMOX1 inhibitor zinc protoporphyrin reduced the ratio of CD163 + HMOX1 + M2 macrophages in mouse BMDM cultures (p < 0.05). HMOX1 expression showed a strong positive correlation with the expression of eotaxin genes (CCL11, CCL24, and CCL26; p < 0.05 respectively).
CONCLUSION: M2 macrophage-derived HMOX1 can be used as an innovative diagnostic signature for CRSwNP, which might be a potential regulator of eosinophilic inflammation.

Keywords:  CD163; HMOX1; M2 macrophages; chronic rhinosinusitis with nasal polyps; diagnostic signature

DOI:  https://doi.org/10.1002/clt2.70014
Science. 2024 Dec 12. eadj3020

Nutrient-driven histone code determines exhausted CD8+ T cell fates.

Shixin Ma, Michael S Dahabieh, Thomas H Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M DeCamp, Brandon M Oswald, Ryan D Sheldon, Abigail E Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G Jones, Susan M Kaech.

Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

DOI: https://doi.org/10.1126/science.adj3020
Microbiol Res. 2024 Dec 06. pii: S0944-5013(24)00396-3. [Epub ahead of print]292 127995

Decoding bacterial communication: Intracellular signal transduction, quorum sensing, and cross-kingdom interactions.

Shuxun Liu, Xujie Feng, Hangjia Zhang, Ping Li, Baoru Yang, Qing Gu.

  This review provides a comprehensive analysis of the intricate architecture of bacterial sensing systems, with a focus on signal transduction mechanisms and their critical roles in microbial physiology. It highlights quorum sensing (QS), quorum quenching (QQ), and quorum sensing interference (QSI) as fundamental processes driving bacterial communication, influencing gene expression, biofilm formation, and interspecies interactions. The analysis explores the importance of diffusible signal factors (DSFs) and secondary messengers such as cAMP and c-di-GMP in modulating microbial behaviors. Additionally, cross-kingdom signaling, where bacterial signals impact host-pathogen dynamics and ecological balance, is systematically reviewed. This review introduces "signalomics", an novel interdisciplinary framework integrating genomics, proteomics, and metabolomics to offer a holistic framework for understanding microbial communication and evolution. These findings hold significant implications for various domains, including food preservation, agriculture, and human health.

Keywords:  Bacterial sensing system; Cross-kingdom signaling; Quorum sensing; Secondary messengers; Signal transduction; Signalomics

DOI:  https://doi.org/10.1016/j.micres.2024.127995
Int Microbiol. 2024 Dec 11.

Screening of lactic acid bacteria from the milk of Sahiwal cows and characterization of their probiotic potential for preventing bovine mastitis.

Nutan Chauhan, Sachin Kumar, Tejshi Chauhan, Ashis Kumar Samanta.

  Antibiotic therapy has been the most popular line of treatment for the control of mastitis worldwide during the last few decades. Alternative and sustainable treatments must be developed because pathogens are becoming more resistant to antibiotics, leading to the development and spread of antimicrobial resistance (AMR). The aim of the current investigation was to isolate lactic acid bacteria (LAB) with probiotic potential that can inhibit mastitis-causing pathogens to prevent bovine mastitis. Milk samples were collected from Sahiwal cows, and a total of 150 bacteria were isolated, of which 76 were found to be catalase negative, and resistant to vancomycin. Twenty-three isolates displayed greater acid and bile tolerance, with > 90% survivability, and were molecularly characterized by 16S rRNA partial sequencing. The autoaggregation percentages for SML7 and SML41 were greater (p<0·05) 80.38±0.19% and 80.28±0.04%, respectively. SML10 (92.04±0.26 μmol/mL) had the highest (p<0.05) ferric-reducing antioxidant power (FRAP) activity, while SML20 (52.1±0.99%) had the highest 1,1 diphenyl 2 picrylhydrazyl (DPPH) scavenging activity. All the strains were nonhemolytic or nonmucinolytic. The highest antimicrobial activity was observed in several strains (SML41, SML63, SML76, and SML60) against common mastitis-causing pathogens, namely, E. coli ATCC25922, Staphylococcus aureus ATCC25923, Enterococcus faecalis NCDC114, Streptococcus agalactiae NCDC208, and Enterococcus faecium NCDC124. The coaggregation efficacy of SML20 with S. aureus was the highest (67.69±1.21%), while SML41 showed the highest (69.75±0.29%) coaggregation efficacy with E. faecalis NCDC114 and SML63 (68.078±0.26) with S. agalactiae NCDC208. Overall, seven distinct lactic acid bacterial clusters were identified by cluster analysis of the phylogenetic tree as follows: Enterococcus hirae (1), Limosilactobacillus reuteri (1), Pediococcus acidilactici (4), Weissella confusa (11), Lactobacillus helveticus (3), Limosilactobacillus balticus (2), and Lacticaseibacillus rhamnosus (1). The Lactobacillus helveticus SML41, Lactobacillus helveticus SML60, Weissella confusa SML61, Lacticaseibacillus rhamnosus SML63, Weissella confusa SML64, and Pediococcus acidilactici SML76 isolates were found to possess the most desirable characteristics of potential probiotics based on principal component analysis (PCA). Therefore, the strains chosen in the current investigation demonstrated techno-functional characteristics that rendered them appropriate for probiotic use to treat and prevent intramammary infections in dairy cattle in a sustainable manner.

Keywords:   Sahiwal cow; Cluster analysis; Lactic acid bacteria; Mastitis; Milk; Probiotics

DOI:  https://doi.org/10.1007/s10123-024-00623-6
Life Sci. 2024 Dec 05. pii: S0024-3205(24)00887-7. [Epub ahead of print] 123297

M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells.

Zhi-Gang Chen, Yu-Tong Xie, Chao Yang, Tong Xiao, Si-Yu Chen, Jun-Hong Wu, Qiao-Nan Guo, Lei Gao.

  Chemotherapy resistance is a significant clinical challenge in the treatment of leukemia. M2 macrophages have been identified as key contributors to the development of chemotherapy resistance in cancer, yet the precise mechanisms by which macrophages regulate this resistance remain elusive. Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy. Collectively, these findings underscore the complex interplay between M2 macrophages, CCL20 signaling, and chemotherapy resistance in AML, highlighting potential therapeutic avenues for intervention.

Keywords:  Acute myeloid leukemia; CCL20; Chemoresistance; Ferroptosis; Macrophages

DOI:  https://doi.org/10.1016/j.lfs.2024.123297
Microbiol Spectr. 2024 Dec 10. e0199624

Palmitoleic acid sensitizes vancomycin-resistant Staphylococcus aureus to vancomycin by outpacing the expression of resistance genes.

Zajeba Tabashsum, Michelle Angeles-Solano, Ashelyn E Sidders, Joshua B Parsons, Sarah E Rowe.

  The rise in antibiotic resistance limits the availability of antibiotics to treat bacterial infections. Despite this, antibiotic development pipelines remain sparse which makes using adjuvants to reverse antibiotic resistance a promising therapeutic strategy. The use of vancomycin, a frontline antibiotic used to treat hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) infections, is complicated by high rates of treatment failure. Vancomycin binds to the D-ala-D-ala terminus of the nascent peptidoglycan precursor lipid II, preventing cell wall biosynthesis. Vancomycin-resistant strains of S. aureus and Enterococci typically express a van gene cluster that is induced in response to vancomycin and results in the synthesis of an alternative lipid precursor with a peptide chain ending in D-ala-D-lac. Vancomycin has low affinity for the D-ala-D-lac terminus, and the bacteria can resume growth even in the presence of an otherwise lethal dose of vancomycin. We previously showed that palmitoleic acid, a host-produced monounsaturated fatty acid, combined with vancomycin led to an accumulation of large fluid patches in the bacterial membrane, resulting in membrane destabilization and cell death. In this study, we observed that palmitoleic acid increases the rate of vancomycin killing by more than 50-fold, compared to vancomycin alone. This rapid bactericidal activity by the combined treatment sensitized vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant Enterococcus (VRE) to vancomycin, likely by outpacing the expression of vancomycin resistance genes. This study represents an important step in the ongoing effort to mitigate antibiotic resistance.IMPORTANCEThe development of antibiotics has transformed medicine, reducing the incidence and severity of bacterial infections and allowing for advancements in healthcare, including invasive surgeries and organ transplants. However, the rise of antibiotic resistance poses a significant threat to these medical advancements, leading to treatment failures that result in increased patient morbidity and mortality, as well as substantial healthcare costs. Vancomycin-resistant Enterococcus (VRE) species are prevalent in hospital settings and chronic infections. Although high-level vancomycin resistance in S. aureus is rare, S. aureus can acquire plasmids expressing vancomycin resistance genes from resistant Enterococcal species during infection, further complicating treatment. In this study, we find that palmitoleic acid increases the rate of vancomycin killing and restores sensitivity to vancomycin-resistant S. aureus (VRSA) and VRE isolates.

Keywords:  Staphylococcus aureus; antibiotic adjuvants; antibiotic resistance

DOI:  https://doi.org/10.1128/spectrum.01996-24
EMBO Rep. 2024 Dec 12.

Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.

Tasuku Nishimura, Takahisa Kouwaki, Ken Takashima, Akie Ochi, Yohana S Mtali, Hiroyuki Oshiumi.

  Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.

Keywords:  Cholesterol; Innate Immunity; RIG-I; Type I Interferon; Virus

DOI:  https://doi.org/10.1038/s44319-024-00346-9
Curr Res Microb Sci. 2024 ;7 100316

Candida albicans enhances Staphylococcus aureus virulence by progressive generation of new phenotypes.

Betsy Verónica Arévalo-Jaimes, Eduard Torrents.

  Candida albicans and Staphylococcus aureus have been co-isolated from several biofilm-associated diseases, including those related to medical devices. This association confers advantages to both microorganisms, resulting in detrimental effects on the host. To elucidate this phenomenon, the present study investigated colony changes derived from non-physical interactions between C. albicans and S. aureus. We performed proximity assays by confronting colonies of the yeast and the bacteria on agar plates at six different distances for 9-10 days. We found that colony variants of S. aureus originated progressively after prolonged exposure to C. albicans proximity, specifically in response to pH neutralization of the media by the fungi. The new phenotypes of S. aureus were more virulent in a Galleria mellonella larvae model compared to colonies grown without C. albicans influence. This event was associated with an upregulation of RNA III and agrA expression, suggesting a role for α-toxin. Our findings indicate that C. albicans enhances S. aureus virulence by inducing the formation of more aggressive colonies. This highlights the importance of understanding the intricate connection between environmental responses, virulence and, fitness in S. aureus pathogenesis.

Keywords:  Agr system; Galleria mellonella; Interkingdom interactions; Pathogenicity; Polymicrobial interactions; Proximity assay; Synergistic effects

DOI:  https://doi.org/10.1016/j.crmicr.2024.100316
Nat Rev Gastroenterol Hepatol. 2024 Dec 11.

Antibiotic-perturbed microbiota and the role of probiotics.

Hania Szajewska, Karen P Scott, Tim de Meij, Sofia K Forslund-Startceva, Rob Knight, Omry Koren, Paul Little, Bradley C Johnston, Jan Łukasik, Jotham Suez, Daniel J Tancredi, Mary Ellen Sanders.

The disruptive effect of antibiotics on the composition and function of the human microbiota is well established. However, the hypothesis that probiotics can help restore the antibiotic-disrupted microbiota has been advanced, with little consideration of the strength of evidence supporting it. Some clinical data suggest that probiotics can reduce antibiotic-related side effects, including Clostridioides difficile-associated diarrhoea, but there are no data that causally link these clinical effects to microbiota protection or recovery. Substantial challenges hinder attempts to address this hypothesis, including the absence of consensus on the composition of a 'normal' microbiota, non-standardized and evolving microbiome measurement methods, and substantial inter-individual microbiota variation. In this Review, we explore these complexities. First, we review the known benefits and risks of antibiotics, the effect of antibiotics on the human microbiota, the resilience and adaptability of the microbiota, and how microbiota restoration might be defined and measured. Subsequently, we explore the evidence for the efficacy of probiotics in preventing disruption or aiding microbiota recovery post-antibiotic treatment. Finally, we offer insights into the current state of research and suggest directions for future research.

DOI: https://doi.org/10.1038/s41575-024-01023-x
JAMA Intern Med. 2024 Dec 09.

When Can a MRSA Nares Swab Guide Antibiotic Stewardship?: What the Nose Knows.

Ashley K Saito, Matthew B Goetz, Simon Wu.

DOI: https://doi.org/10.1001/jamainternmed.2024.6436
Redox Biol. 2024 Dec 09. pii: S2213-2317(24)00441-5. [Epub ahead of print]79 103463

AKRs confer oligodendrocytes resistance to differentiation-stimulated ferroptosis.

Valentina Saverio, Emanuele Ferrario, Romina Monzani, Mara Gagliardi, Francesco Favero, Davide Corà, Claudio Santoro, Marco Corazzari.

  Ferroptosis is a recently characterized form of cell death that has gained attention for its roles in both pathological and physiological contexts. The existence of multiple anti-ferroptotic pathways in both neoplastic and healthy cells, along with the critical regulation of iron metabolism involved in lipid peroxides (lipid-ROS) production-the primary mediators of this cell death process-underscores the necessity of precisely controlling or preventing accidental/unwanted ferroptosis. Conversely, dysregulated iron metabolism and alterations in the expression or activity of key anti-ferroptotic components are linked to the development and progression of various human diseases, including multiple sclerosis (MS). In MS, the improper activation of ferroptosis has been associated with the progressive loss of myelinating oligodendrocytes (myOLs). Our study demonstrates that the physiological and maturation-dependent increase in iron accumulation within oligodendrocytes acts as a pro-ferroptotic signal, countered by the concurrent expression of AKR1C1. Importantly, MS-related neuroinflammation contributes to the down-regulation of AKR1C1 through miRNA-mediated mechanisms, rendering mature oligodendrocytes more vulnerable to ferroptosis. Together, these findings highlight the role of ferroptosis in MS-associated oligodendrocyte loss and position AKR1C1 as a potential therapeutic target for preserving oligodendrocyte integrity and supporting neuronal function in MS patients.

Keywords:  AKR1C1; Aldo-keto reductase; Ferroptosis; Multiple sclerosis; miRNA

DOI:  https://doi.org/10.1016/j.redox.2024.103463
Infect Genet Evol. 2024 Dec 10. pii: S1567-1348(24)00155-2. [Epub ahead of print] 105703

BCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases.

Nilofer Naqvi, Yashika Ahuja, Sheeba Zarin, Anwar Alam, Waseem Ali, Mohd Shariq, Seyed E Hasnain, Nasreen Z Ehtesham.

  The BCG vaccine represents a significant milestone in the prevention of tuberculosis (TB), particularly in children. Researchers have been developing recombinant BCG (rBCG) variants that can trigger lasting memory responses, thereby enhancing protection against TB in adults. The breakdown of immune surveillance is a key link between TB and other communicable and non-communicable diseases. Notably, TB is more prevalent among people with comorbidities such as HIV, diabetes, cancer, influenza, COVID-19, and autoimmune disorders. rBCG formulations have the potential to address both TB and HIV co-pandemics. TB increases the risk of lung cancer and immunosuppression caused by cancer can reactivate latent TB infections. Moreover, BCG's efficacy extends to bladder cancer treatment and blood glucose regulation in patients with diabetes and TB. Additionally, BCG provides cross-protection against unrelated pathogens, emphasizing the importance of BCG-induced trained immunity in COVID-19 and other respiratory diseases. Furthermore, BCG reduced the severity of pulmonary TB-induced influenza virus infections. Recent studies have proposed innovations in BCG delivery, revaccination, and attenuation techniques. Disease-centered research has highlighted the immunomodulatory effects of BCG on TB, HIV, cancer, diabetes, COVID-19, and autoimmune diseases. The complex relationship between TB and comorbidities requires a nuanced re-evaluation to understand the shared attributes regulated by BCG. This review assessed the interconnected relationships influenced by BCG administration in TB and related disorders, recommending the expanded use of rBCG in healthcare. Collaboration among vaccine research stakeholders is vital to enhance BCG's efficacy against global health challenges.

Keywords:  Adaptive immunity; Bladder cancer; Comorbidity; Heterologous protection; Innate immunity; Trained-immunity

DOI:  https://doi.org/10.1016/j.meegid.2024.105703