bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒05‒05
43 papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.
  2. Staphylococcus aureus membrane vesicles: an evolving story.
  3. Monocytes and macrophages: Origin, homing, differentiation, and functionality during inflammation.
  4. Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.
  5. Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival.
  6. N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
  7. Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.
  8. Coordinated chemokine expression defines macrophage subsets across tissues.
  9. Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.
  10. Toll-like receptors in health and disease.
  11. In vitro co-culture of Clostridium scindens with primary human colonic epithelium protects the epithelium against Staphylococcus aureus.
  12. MNDA, a PYHIN factor involved in transcriptional regulation and apoptosis control in leukocytes.
  13. Human nasal microbiota shifts in healthy and chronic respiratory disease conditions.
  14. Multitasking within the airway epithelium.
  15. The Role of Macrophage Death in Periodontitis: A Review.
  16. A survey of multiple candidate probiotic bacteria reveals specificity in the ability to modify the effects of key wound pathogens.
  17. Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells.
  18. Widespread alterations in systemic immune profile are linked to lung function heterogeneity and airway microbes in cystic fibrosis.
  19. Direct Salmonella injection into enteroid cells allows the study of host-pathogen interactions in the cytosol with high spatiotemporal resolution.
  20. Targeting the TRAF3-ULK1-NLRP3 regulatory axis to control alveolar macrophage pyroptosis in acute lung injury.
  21. Distinct fibroblast functions associated with fibrotic and immune-mediated inflammatory diseases and their implications for therapeutic development.
  22. Oral bacteria relative abundance in faeces increases due to gut microbiota depletion and is linked with patient outcomes.
  23. BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms.
  24. The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
  25. The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps.
  26. CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.
  27. Probiotics: Shaping the gut immunological responses.
  28. Induction of trained immunity using β-glucan and its protective responses in Nile tilapia, Oreochromis niloticus.
  29. CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment.
  30. DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways.
  31. An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection.
  32. Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.
  33. Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.
  34. Nasal Staphylococcus aureus Carriage and Antimicrobial Resistance Profiles Among Community-Dwelling Adults in Jiangsu, China.
  35. S100a9 might act as a modulator of the Toll-like receptor 4 transduction pathway in chronic rhinosinusitis with nasal polyps.
  36. Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.
  37. Dad's microbiome can affect offspring's health - in mice.
  38. Exploiting cooperative pathogen behaviour for enhanced antibiotic potency: A Trojan horse approach.
  39. Myeloid-derived suppressor cells in influenza virus-induced asthma exacerbation.
  40. Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
  41. Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type-specific HIV latency reactivation.
  42. Baseline JAK-STAT signaling maintains immune cell homeostasis.
  43. The ever-changing microenvironment of Staphylococcus aureus in cutaneous infections.
  1. Nat Commun. 2024 Apr 30. 15(1): 3666
    Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.
    Sungmin Moon, Seunghan Han, In-Hwan Jang, Jaechan Ryu, Min-Seok Rha, Hyung-Ju Cho, Sang Sun Yoon, Ki Taek Nam, Chang-Hoon Kim, Man-Seong Park, Je Kyung Seong, Won-Jae Lee, Joo-Heon Yoon, Youn Wook Chung, Ji-Hwan Ryu.
      Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.
    DOI:  https://doi.org/10.1038/s41467-024-47963-5
  2. Trends Microbiol. 2024 Apr 26. pii: S0966-842X(24)00088-X. [Epub ahead of print]
    Staphylococcus aureus membrane vesicles: an evolving story.
    Xiaogang Wang, Jean C Lee.
      Staphylococcus aureus is an important bacterial pathogen that causes a wide variety of human diseases in community and hospital settings. S. aureus employs a diverse array of virulence factors, both surface-associated and secreted, to promote colonization, infection, and immune evasion. Over the past decade, a growing body of research has shown that S. aureus generates extracellular membrane vesicles (MVs) that package a variety of bacterial components, many of which are virulence factors. In this review, we summarize recent advances in our understanding of S. aureus MVs and highlight their biogenesis, cargo, and potential role in the pathogenesis of staphylococcal infections. Lastly, we present some emerging questions in the field.
    Keywords:  Staphylococcus aureus; biogenesis; cargo; extracellular membrane vesicles; vaccine; virulence factors
    DOI:  https://doi.org/10.1016/j.tim.2024.04.003
  3. Heliyon. 2024 Apr 30. 10(8): e29686
    Monocytes and macrophages: Origin, homing, differentiation, and functionality during inflammation.
    Shiba Prasad Dash, Saloni Gupta, Pranita P Sarangi.
      Monocytes and macrophages are essential components of innate immune system and have versatile roles in homeostasis and immunity. These phenotypically distinguishable mononuclear phagocytes play distinct roles in different stages, contributing to the pathophysiology in various forms making them a potentially attractive therapeutic target in inflammatory conditions. Several pieces of evidence have supported the role of different cell surface receptors expressed on these cells and their downstream signaling molecules in initiating and perpetuating the inflammatory response. In this review, we discuss the current understanding of the monocyte and macrophage biology in inflammation, highlighting the role of chemoattractants, inflammasomes, and integrins in the function of monocytes and macrophages during events of inflammation. This review also covers the recent therapeutic interventions targeting these mononuclear phagocytes at the cellular and molecular levels.
    Keywords:  Inflammasomes; Inflammation; Integrins; Macrophages; Metabolic reprogramming; Monocytes
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e29686
  4. PLoS Pathog. 2024 May 03. 20(5): e1012205
    Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.
    Weihao Zheng, I-Chang Chang, Jason Limberis, Jonathan M Budzik, Beth Shoshana Zha, Zachary Howard, Lucas Chen, Joel D Ernst.
      Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.
    DOI:  https://doi.org/10.1371/journal.ppat.1012205
  5. mBio. 2024 Apr 29. e0034624
    Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival.
    Joana Alves, Manouk Vrieling, Natalie Ring, Gonzalo Yebra, Amy Pickering, Tomasz K Prajsnar, Stephen A Renshaw, J Ross Fitzgerald.
      Staphylococcus aureus is a major pathogen associated with important diseases in humans and animals. Macrophages are a key component of the innate immune response to S. aureus infection and play a major role in disease outcomes. To investigate the adaptive evolution of S. aureus in response to macrophages, we developed an experimental infection assay. S. aureus strains representing major human epidemic clones were passaged many times in a macrophage cell line, accumulating mutations in an array of genomic loci. Phenotypic analysis revealed the emergence of a lineage exhibiting increased survival in macrophages and human blood, and resistance to vancomycin. The evolved lineage exhibited a previously undescribed small colony variant (SCV) phenotype characterized by hyper-pigmentation, which resulted from a missense mutation in rsbW. Notably, the novel SCV was a conditional adaptive trait that was unstable in nutrient-replete conditions in vitro, rapidly converting from hyper-pigmented SCV to a non-pigmented large colony variant via spontaneous sigB deletion events. Importantly, we identified similar deletions in the genome sequences of a limited number of clinical S. aureus isolates from public databases, indicating that related events may occur during clinical infection. Experimental infection of zebrafish did not reveal a difference in virulence between parent and novel SCV but demonstrated an in vivo fitness cost for the compensatory sigB deletion events. Taken together, we report an experimental evolutionary approach for investigating bacterial innate immune cell interactions, revealing a conditional adaptation that promotes S. aureus survival in macrophages and resistance to vancomycin.IMPORTANCE: Staphylococcus aureus is an important human bacterial pathogen. The host response to S. aureus involves the production of innate immune cells such as macrophages which are important for fighting infection. Here we report a new model of experimental evolution for studying how S. aureus can evade killing by macrophages. We identified a novel adaptive phenotype that promotes survival in macrophages and blood and resistance to antibiotics. The phenotype is lost rapidly upon growth in nutrient-rich conditions via disruption of the alternative sigma factor sigB, revealing a conditional niche-specific fitness advantage. Genomic analysis of clinical isolates suggests similar adaptations may occur during human infections. Our model may be used broadly to identify adaptations of S. aureus to the innate immune response.
    Keywords:  Staphylococcus aureus; antibiotic resistance; evolution; macrophages
    DOI:  https://doi.org/10.1128/mbio.00346-24
  6. Immunity. 2024 Apr 26. pii: S1074-7613(24)00209-7. [Epub ahead of print]
    N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
    Alexander D Gitlin, Allie Maltzman, Yuzuka Kanno, Klaus Heger, Rohit Reja, Alexander F Schubert, Linsey J Wierciszewski, Homer Pantua, Sharookh B Kapadia, Seth F Harris, Joshua D Webster, Kim Newton, Vishva M Dixit.
      The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.
    Keywords:  Toll-like receptors; cytokines; inflammation; innate immunity; signal transduction
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.004
  7. Elife. 2024 Apr 30. pii: RP89098. [Epub ahead of print]12
    Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.
    Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L DuMont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, Bo Shopsin.
      The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.
    Keywords:  Staphylococcus aureus; agr; infectious disease; microbiology; peroxide (H2O2); quorum-sensing; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.7554/eLife.89098
  8. Nat Immunol. 2024 May 02.
    Coordinated chemokine expression defines macrophage subsets across tissues.
    Xin Li, Arlind B Mara, Shawn C Musial, Fred W Kolling, Sophie L Gibbings, Nikita Gerebtsov, Claudia V Jakubzick.
      Lung-resident macrophages, which include alveolar macrophages and interstitial macrophages (IMs), exhibit a high degree of diversity, generally attributed to different activation states, and often complicated by the influx of monocytes into the pool of tissue-resident macrophages. To gain a deeper insight into the functional diversity of IMs, here we perform comprehensive transcriptional profiling of resident IMs and reveal ten distinct chemokine-expressing IM subsets at steady state and during inflammation. Similar IM subsets that exhibited coordinated chemokine signatures and differentially expressed genes were observed across various tissues and species, indicating conserved specialized functional roles. Other macrophage types shared specific IM chemokine profiles, while also presenting their own unique chemokine signatures. Depletion of CD206hi IMs in Pf4creR26EYFP+DTR and Pf4creR26EYFPCx3cr1DTR mice led to diminished inflammatory cell recruitment, reduced tertiary lymphoid structure formation and fewer germinal center B cells in models of allergen- and infection-driven inflammation. These observations highlight the specialized roles of IMs, defined by their coordinated chemokine production, in regulating immune cell influx and organizing tertiary lymphoid tissue architecture.
    DOI:  https://doi.org/10.1038/s41590-024-01826-9
  9. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2321836121
    Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.
    José L Fachi, Blanda Di Luccia, Susan Gilfillan, Hao-Wei Chang, Christina Song, Jiye Cheng, Marina Cella, Marco Aurelio Vinolo, Jeffrey I Gordon, Marco Colonna.
      Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.
    Keywords:  Clostridioides difficile colitis; IL-22 signaling; epithelial barrier; gut microbiota composition; short-chain fatty acids
    DOI:  https://doi.org/10.1073/pnas.2321836121
  10. MedComm (2020). 2024 May;5(5): e549
    Toll-like receptors in health and disease.
    Kunyu Wang, Hanyao Huang, Qi Zhan, Haoran Ding, Yi Li.
      Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.
    Keywords:  cancer; clinical treatment; disease; innate immunity; toll‐like receptors
    DOI:  https://doi.org/10.1002/mco2.549
  11. Front Bioeng Biotechnol. 2024 ;12 1382389
    In vitro co-culture of Clostridium scindens with primary human colonic epithelium protects the epithelium against Staphylococcus aureus.
    Hao Wang, Raehyun Kim, Yuli Wang, Kathleen L Furtado, Christopher E Sims, Rita Tamayo, Nancy L Allbritton.
      A complex and dynamic network of interactions exists between human gastrointestinal epithelium and intestinal microbiota. Therefore, comprehending intestinal microbe-epithelial cell interactions is critical for the understanding and treatment of intestinal diseases. Primary human colonic epithelial cells derived from a healthy human donor were co-cultured with Clostridium scindens (C. scindens), a probiotic obligate anaerobe; Staphylococcus aureus (S. aureus), a facultative anaerobe and intestinal pathogen; or both bacterial species in tandem. The co-culture hanging basket platform used for these experiments possessed walls of controlled oxygen (O2) permeability to support the formation of an O2 gradient across the intestinal epithelium using cellular O2 consumption, resulting in an anaerobic luminal and aerobic basal compartment. Both the colonic epithelial cells and C. scindens remained viable over 48 h during co-culture. In contrast, co-culture with S. aureus elicited significant damage to colonic epithelial cells within 24 h. To explore the influence of the intestinal pathogen on the epithelium in the presence of the probiotic bacteria, colonic epithelial cells were inoculated sequentially with the two bacterial species. Under these conditions, C. scindens was capable of repressing the production of S. aureus enterotoxin. Surprisingly, although C. scindens converted cholic acid to secondary bile acids in the luminal medium, the growth of S. aureus was not significantly inhibited. Nevertheless, this combination of probiotic and pathogenic bacteria was found to benefit the survival of the colonic epithelial cells compared with co-culture of the epithelial cells with S. aureus alone. This platform thus provides an easy-to-use and low-cost tool to study the interaction between intestinal bacteria and colonic cells in vitro to better understand the interplay of intestinal microbiota with human colonic epithelium.
    Keywords:  bile acid; enterotoxin; gut microbiome; interactions; intestine; multi-species culture; oxygen gradient
    DOI:  https://doi.org/10.3389/fbioe.2024.1382389
  12. Front Immunol. 2024 ;15 1395035
    MNDA, a PYHIN factor involved in transcriptional regulation and apoptosis control in leukocytes.
    Stefania Bottardi, Taylorjade Layne, Ailyn C Ramòn, Norreen Quansah, Hugo Wurtele, El Bachir Affar, Eric Milot.
      Inflammation control is critical during the innate immune response. Such response is triggered by the detection of molecules originating from pathogens or damaged host cells by pattern-recognition receptors (PRRs). PRRs subsequently initiate intra-cellular signalling through different pathways, resulting in i) the production of inflammatory cytokines, including type I interferon (IFN), and ii) the initiation of a cascade of events that promote both immediate host responses as well as adaptive immune responses. All human PYRIN and HIN-200 domains (PYHIN) protein family members were initially proposed to be PRRs, although this view has been challenged by reports that revealed their impact on other cellular mechanisms. Of relevance here, the human PYHIN factor myeloid nuclear differentiation antigen (MNDA) has recently been shown to directly control the transcription of genes encoding factors that regulate programmed cell death and inflammation. While MNDA is mainly found in the nucleus of leukocytes of both myeloid (neutrophils and monocytes) and lymphoid (B-cell) origin, its subcellular localization has been shown to be modulated in response to genotoxic agents that induce apoptosis and by bacterial constituents, mediators of inflammation. Prior studies have noted the importance of MNDA as a marker for certain forms of lymphoma, and as a clinical prognostic factor for hematopoietic diseases characterized by defective regulation of apoptosis. Abnormal expression of MNDA has also been associated with altered levels of cytokines and other inflammatory mediators. Refining our comprehension of the regulatory mechanisms governing the expression of MNDA and other PYHIN proteins, as well as enhancing our definition of their molecular functions, could significantly influence the management and treatment strategies of numerous human diseases. Here, we review the current state of knowledge regarding PYHIN proteins and their role in innate and adaptive immune responses. Emphasis will be placed on the regulation, function, and relevance of MNDA expression in the control of gene transcription and RNA stability during cell death and inflammation.
    Keywords:  MNDA; PYHIN factors; apoptosis; genotoxic stress; innate immunity; transcription control
    DOI:  https://doi.org/10.3389/fimmu.2024.1395035
  13. BMC Microbiol. 2024 Apr 27. 24(1): 150
    Human nasal microbiota shifts in healthy and chronic respiratory disease conditions.
    Aleksandras Konovalovas, Julija Armalytė, Laurita Klimkaitė, Tomas Liveikis, Brigita Jonaitytė, Edvardas Danila, Daiva Bironaitė, Diana Mieliauskaitė, Edvardas Bagdonas, Rūta Aldonytė.
      BACKGROUND: An increasing number of studies investigate various human microbiotas and their roles in the development of diseases, maintenance of health states, and balanced signaling towards the brain. Current data demonstrate that the nasal microbiota contains a unique and highly variable array of commensal bacteria and opportunistic pathogens. However, we need to understand how to harness current knowledge, enrich nasal microbiota with beneficial microorganisms, and prevent pathogenic developments.RESULTS: In this study, we have obtained nasal, nasopharyngeal, and bronchoalveolar lavage fluid samples from healthy volunteers and patients suffering from chronic respiratory tract diseases for full-length 16 S rRNA sequencing analysis using Oxford Nanopore Technologies. Demographic and clinical data were collected simultaneously. The microbiome analysis of 97 people from Lithuania suffering from chronic inflammatory respiratory tract disease and healthy volunteers revealed that the human nasal microbiome represents the microbiome of the upper airways well.
    CONCLUSIONS: The nasal microbiota of patients was enriched with opportunistic pathogens, which could be used as indicators of respiratory tract conditions. In addition, we observed that a healthy human nasal microbiome contained several plant- and bee-associated species, suggesting the possibility of enriching human nasal microbiota via such exposures when needed. These candidate probiotics should be investigated for their modulating effects on airway and lung epithelia, immunogenic properties, neurotransmitter content, and roles in maintaining respiratory health and nose-brain interrelationships.
    Keywords:  Biomarkers; Nasal microbiota; Upper respiratory tract
    DOI:  https://doi.org/10.1186/s12866-024-03294-5
  14. Eur Respir J. 2024 May;pii: 2302223. [Epub ahead of print]63(5):
    Multitasking within the airway epithelium.
    James E Gern, Carole Ober.
      
    DOI:  https://doi.org/10.1183/13993003.02223-2023
  15. Inflammation. 2024 May 01.
    The Role of Macrophage Death in Periodontitis: A Review.
    Wen Luo, Chengying Du, Hsiuwei Huang, Jie Kong, Ziming Ge, Li Lin, Hongyan Wang.
      Periodontitis, an infectious inflammatory disease influenced by various factors, disrupts the delicate balance between the host microbiota and immunity. The resulting excessive immune response exacerbates the progressive destruction of the supporting periodontal tissue. Macrophages are essential elements of the host innate immune system. They are pivotal components in the periodontal immune microenvironment and actively participate in both physiological and pathological processes of periodontal tissue. When confronted with periodontitis-related irritant factors, macrophages may differentiate to pro- or anti-inflammatory subtypes that affect tissue homeostasis. Additionally, macrophages may die in response to bacterial infections, potentially affecting the severity of periodontitis. This article reviews the typical mechanisms underlying macrophage death and its effects on periodontitis. We describe five forms of macrophage death in periodontitis: apoptosis, pyroptosis, necroptosis, ferroptosis, and ETosis. Our review of macrophage death in the pathophysiology of periodontitis enhances comprehension of the pathogenesis of periodontitis that will be useful for clinical practice. Although our review elucidates the complex mechanisms by which macrophage death and inflammatory pathways perpetuate periodontitis, unresolved issues remain, necessitating further research.
    Keywords:  apoptosis; autophagy; extracellular traps; ferroptosis.; oral microbiota; pyroptosis
    DOI:  https://doi.org/10.1007/s10753-024-02015-4
  16. Microbiol Spectr. 2024 May 03. e0034724
    A survey of multiple candidate probiotic bacteria reveals specificity in the ability to modify the effects of key wound pathogens.
    Muna Alhubail, Andrew J McBain, Catherine A O'Neill.
      We have evaluated the inhibitory effects of supernatants and lysates derived from several candidate probiotics, on the growth and biofilm formation of wound pathogens, and their ability to protect human primary epidermal keratinocytes from the toxic effects of pathogens. Supernatants (neutralized and non-neutralized) and lysates (via sonication) from Lactiplantibacillus plantarum, Limosilactobacillus reuteri, Bifidobacterium longum, Lacticaseibacillus rhamnosus GG, and Escherichia coli Nissle 1917 were tested for their inhibitory effects against Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumanni. The supernatants of L. plantarum, L. rhamnosus, B. longum, and L. rhamnosus GG reduced the growth of S. aureus, E. coli, and A. baumanni. B. longum additionally inhibited P. aeruginosa growth. However, neutralized Lactobacillus supernatants did not inhibit growth and in some cases were stimulatory. Lysates of L. plantarum and L. reuteri inhibited S. pyogenes while B. longum lysates inhibited E. coli and S. aureus growth. E. coli Nissle 1917 lysates enhanced the growth of S. pyogenes and P. aeruginosa. Biofilm formation by E. coli was reduced by lysates of L. reuteri and neutralized supernatants of all candidate probiotics. P. aeruginosa biofilm formation was reduced by E. coli Nissle supernatant but increased by L. plantarum, L. reuteri, and Bifidobacterium longum lysates. L. reuteri decreased the toxic effects of S. aureus on keratinocytes while E. coli Nissle 1917 lysates protected keratinocytes from S. pyogenes toxicity. In conclusion, lactobacilli and E. coli Nissle lysates confer inhibitory effects on pathogenic growth independently of acidification and may beneficially alter the outcome of interactions between host cell-pathogen in a species-specific manner.IMPORTANCEOne of the attributes of probiotics is their ability to inhibit pathogens. For this reason, many lactobacilli have been investigated for their effects as potential topical therapeutics against skin pathogens. However, this field is in its infancy. Even though probiotics are known to be safe when taken orally, the potential safety concerns when applied to potentially compromised skin are unknown. For this reason, we believe that extracts of probiotics will offer advantages over the use of live bacteria. In this study, we have surveyed five candidate probiotics, when used as extracts, in terms of their effects against common wound pathogens. Our data demonstrate that some probiotic extracts promote the growth of pathogens and highlight the need for careful selection of species and strains when probiotics are to be used topically.
    Keywords:  keratinocyte; lactic acid bacteria; probiotic; wound pathogen
    DOI:  https://doi.org/10.1128/spectrum.00347-24
  17. Clin Exp Immunol. 2024 May 02. pii: uxae034. [Epub ahead of print]
    Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells.
    Vasista Adiga, Hima Bindhu, Asma Ahmed, Nirutha Chetan Kumar, Himanshu Tripathi, George D'Souza, Mary Dias, Sudarshan Shivalingaiah, Srishti Rao, K N Shanti, Catherine Hawrylowicz, Pratibha Dwarkanath, Annapurna Vyakarnam.
      Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value<0.05) identified bacterial PAMPs induced higher concentrations of IL-1β, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1β in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.
    Keywords:  Cytokines; Monocytes; Neonates; Pathogen-associated molecular patterns (PAMPs); Toll-like receptors (TLRs)
    DOI:  https://doi.org/10.1093/cei/uxae034
  18. J Cyst Fibros. 2024 May 02. pii: S1569-1993(24)00059-6. [Epub ahead of print]
    Widespread alterations in systemic immune profile are linked to lung function heterogeneity and airway microbes in cystic fibrosis.
    Elio Rossi, Mads Lausen, Nina Friesgaard Øbro, Antonella Colque, Bibi Uhre Nielsen, Rikke Møller, Camilla de Gier, Annemette Hald, Marianne Skov, Tacjana Pressler, Søren Molin, Sisse Rye Ostrowski, Hanne Vibeke Marquart, Helle Krogh Johansen.
      BACKGROUND: Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated.METHODS: Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression.
    RESULTS: In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs.
    CONCLUSION: The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management.
    Keywords:  Adaptive immunity; Cystic fibrosis; Immune dysregulation; Infections; Innate immunity; Lung microbiome
    DOI:  https://doi.org/10.1016/j.jcf.2024.04.015
  19. PLoS Biol. 2024 Apr;22(4): e3002597
    Direct Salmonella injection into enteroid cells allows the study of host-pathogen interactions in the cytosol with high spatiotemporal resolution.
    Chantal Ernst, Patrick R Andreassen, Gabriel H Giger, Bidong D Nguyen, Christoph G Gäbelein, Orane Guillaume-Gentil, Stefan A Fattinger, Mikael E Sellin, Wolf-Dietrich Hardt, Julia A Vorholt.
      Intestinal epithelial cells (IECs) play pivotal roles in nutrient uptake and in the protection against gut microorganisms. However, certain enteric pathogens, such as Salmonella enterica serovar Typhimurium (S. Tm), can invade IECs by employing flagella and type III secretion systems (T3SSs) with cognate effector proteins and exploit IECs as a replicative niche. Detection of flagella or T3SS proteins by IECs results in rapid host cell responses, i.e., the activation of inflammasomes. Here, we introduce a single-cell manipulation technology based on fluidic force microscopy (FluidFM) that enables direct bacteria delivery into the cytosol of single IECs within a murine enteroid monolayer. This approach allows to specifically study pathogen-host cell interactions in the cytosol uncoupled from preceding events such as docking, initiation of uptake, or vacuole escape. Consistent with current understanding, we show using a live-cell inflammasome reporter that exposure of the IEC cytosol to S. Tm induces NAIP/NLRC4 inflammasomes via its known ligands flagellin and T3SS rod and needle. Injected S. Tm mutants devoid of these invasion-relevant ligands were able to grow in the cytosol of IECs despite the absence of T3SS functions, suggesting that, in the absence of NAIP/NLRC4 inflammasome activation and the ensuing cell death, no effector-mediated host cell manipulation is required to render the epithelial cytosol growth-permissive for S. Tm. Overall, the experimental system to introduce S. Tm into single enteroid cells enables investigations into the molecular basis governing host-pathogen interactions in the cytosol with high spatiotemporal resolution.
    DOI:  https://doi.org/10.1371/journal.pbio.3002597
  20. Acta Biochim Biophys Sin (Shanghai). 2024 Apr 29.
    Targeting the TRAF3-ULK1-NLRP3 regulatory axis to control alveolar macrophage pyroptosis in acute lung injury.
    Lei Jiang, Chunlin Ye, Yunhe Huang, Zhi Hu, Guangxia Wei.
      Acute lung injury (ALI) is a serious condition characterized by damage to the lungs. Recent research has revealed that activation of the NLRP3 inflammasome in alveolar macrophages, a type of immune cell in the lungs, plays a key role in the development of ALI. This process, known as pyroptosis, contributes significantly to ALI pathogenesis. Researchers have conducted comprehensive bioinformatics analyses and identified 15 key genes associated with alveolar macrophage pyroptosis in ALI. Among these, NLRP3 has emerged as a crucial regulator. This study further reveal that the ULK1 protein diminishes the expression of NLRP3, thereby reducing the immune response of alveolar macrophages and mitigating ALI. Conversely, TRAF3, another protein, is found to inhibit ULK1 through a process called ubiquitination, leading to increased activation of the NLRP3 inflammasome and exacerbation of ALI. This TRAF3-mediated suppression of ULK1 and subsequent activation of NLRP3 are confirmed through various in vitro and in vivo experiments. The presence of abundant M0 and M1 alveolar macrophages in the ALI tissue samples further support these findings. This research highlights the TRAF3-ULK1-NLRP3 regulatory axis as a pivotal pathway in ALI development and suggests that targeting this axis could be an effective therapeutic strategy for ALI treatment.
    Keywords:  NLRP3; TRAF3; ULK1; acute lung injury; alveolar macrophage; pyroptosis; sequence read archive database
    DOI:  https://doi.org/10.3724/abbs.2024035
  21. F1000Res. 2024 ;13 54
    Distinct fibroblast functions associated with fibrotic and immune-mediated inflammatory diseases and their implications for therapeutic development.
    Alexander M S Barron, Thomas Fabre, Saurav De.
      Fibroblasts are ubiquitous cells that can adopt many functional states. As tissue-resident sentinels, they respond to acute damage signals and shape the earliest events in fibrotic and immune-mediated inflammatory diseases. Upon sensing an insult, fibroblasts produce chemokines and growth factors to organize and support the response. Depending on the size and composition of the resulting infiltrate, these activated fibroblasts may also begin to contract or relax thus changing local stiffness within the tissue. These early events likely contribute to the divergent clinical manifestations of fibrotic and immune-mediated inflammatory diseases. Further, distinct changes to the cellular composition and signaling dialogue in these diseases drive progressive fibroblasts specialization. In fibrotic diseases, fibroblasts support the survival, activation and differentiation of myeloid cells, granulocytes and innate lymphocytes, and produce most of the pathogenic extracellular matrix proteins. Whereas, in immune-mediated inflammatory diseases, sequential accumulation of dendritic cells, T cells and B cells programs fibroblasts to support local, destructive adaptive immune responses. Fibroblast specialization has clear implications for the development of effective induction and maintenance therapies for patients with these clinically distinct diseases.
    Keywords:  Fibroblast; autoimmunity; cytokine; fibrosis; inflammation; therapy
    DOI:  https://doi.org/10.12688/f1000research.143472.1
  22. Nat Microbiol. 2024 May 02.
    Oral bacteria relative abundance in faeces increases due to gut microbiota depletion and is linked with patient outcomes.
    Chen Liao, Thierry Rolling, Ana Djukovic, Teng Fei, Vishwas Mishra, Hongbin Liu, Chloe Lindberg, Lei Dai, Bing Zhai, Jonathan U Peled, Marcel R M van den Brink, Tobias M Hohl, Joao B Xavier.
      The detection of oral bacteria in faecal samples has been associated with inflammation and intestinal diseases. The increased relative abundance of oral bacteria in faeces has two competing explanations: either oral bacteria invade the gut ecosystem and expand (the 'expansion' hypothesis), or oral bacteria transit through the gut and their relative increase marks the depletion of other gut bacteria (the 'marker' hypothesis). Here we collected oral and faecal samples from mouse models of gut dysbiosis (antibiotic treatment and DSS-induced colitis) and used 16S ribosomal RNA sequencing to determine the abundance dynamics of oral bacteria. We found that the relative, but not absolute, abundance of oral bacteria increases, reflecting the 'marker' hypothesis. Faecal microbiome datasets from diverse patient cohorts, including healthy individuals and patients with allogeneic haematopoietic cell transplantation or inflammatory bowel disease, consistently support the 'marker' hypothesis and explain associations between oral bacterial abundance and patient outcomes consistent with depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and could potentially identify cases where therapies are needed to rebuild the resident microbiome rather than protect against invading oral bacteria.
    DOI:  https://doi.org/10.1038/s41564-024-01680-3
  23. J Immunol. 2024 Apr 29. pii: ji2200819. [Epub ahead of print]
    BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms.
    Skyler V Hendrix, Yassin Mreyoud, Michael E McNehlan, Asya Smirnov, Sthefany M Chavez, Brian Hie, Megan M Chamberland, Tara R Bradstreet, Ashlee M Webber, Darren Kreamalmeyer, Reshma Taneja, Bryan D Bryson, Brian T Edelson, Christina L Stallings.
      Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to M. tuberculosis infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to M. tuberculosis infection, but how BHLHE40 impacts macrophage and dendritic cell responses to M. tuberculosis is unknown. In this study, we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a proinflammatory state and better control of M. tuberculosis infection. Loss of Bhlhe40 expression in murine bone marrow-derived myeloid cells cultured in the presence of GM-CSF results in lower levels of proinflammatory associated signaling molecules IL-1β, IL-6, IL-12, TNF-α, inducible NO synthase, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory-associated molecules MCP-1 and IL-10 following exposure to heat-killed M. tuberculosis. Deletion of Il10 in Bhlhe40-/- myeloid cells restored some, but not all, proinflammatory signals, demonstrating that BHLHE40 promotes proinflammatory responses via both IL-10-dependent and -independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of M. tuberculosis-infected Bhlhe40-/- mice exhibit defects in inducible NO synthase production compared with infected wild-type mice, supporting that BHLHE40 promotes proinflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during M. tuberculosis infection in vivo.
    DOI:  https://doi.org/10.4049/jimmunol.2200819
  24. Immunol Rev. 2024 Apr 29.
    The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
    Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu.
      White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.
    Keywords:  immunity; macrophage; metabolism; obesity; white adipose tissue
    DOI:  https://doi.org/10.1111/imr.13338
  25. Front Immunol. 2024 ;15 1356298
    The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps.
    Claus Bachert, Alexandra Hicks, Simon Gane, Anju T Peters, Philippe Gevaert, Scott Nash, Julie E Horowitz, Harry Sacks, Juby A Jacob-Nara.
      Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.
    Keywords:  CRSwNP; biologic; chronic rhinosinusitis with nasal polyps; cytokine; interleukin-13; interleukin-4; interleukin-4 receptor; type 2 inflammation
    DOI:  https://doi.org/10.3389/fimmu.2024.1356298
  26. Front Physiol. 2024 ;15 1385661
    CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.
    Min Wu, Jeng-Haur Chen.
      Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.
    Keywords:  CFTR; airway epithelia; bacterial infection; bicarbonate; cystic fibrosis; mucus
    DOI:  https://doi.org/10.3389/fphys.2024.1385661
  27. World J Gastroenterol. 2024 Apr 21. 30(15): 2096-2108
    Probiotics: Shaping the gut immunological responses.
    Eirini Filidou, Leonidas Kandilogiannakis, Anne Shrewsbury, George Kolios, Katerina Kotzampassi.
      Probiotics are live microorganisms exerting beneficial effects on the host's health when administered in adequate amounts. Among the most popular and adequately studied probiotics are bacteria from the families Lactobacillaceae, Bifidobacteriaceae and yeasts. Most of them have been shown, both in vitro and in vivo studies of intestinal inflammation models, to provide favorable results by means of improving the gut microbiota composition, promoting the wound healing process and shaping the immunological responses. Chronic intestinal conditions, such as inflammatory bowel diseases (IBD), are characterized by an imbalance in microbiota composition, with decreased diversity, and by relapsing and persisting inflammation, which may lead to mucosal damage. Although the results of the clinical studies investigating the effect of probiotics on patients with IBD are still controversial, it is without doubt that these microorganisms and their metabolites, now named postbiotics, have a positive influence on both the host's microbiota and the immune system, and ultimately alter the topical tissue microenvironment. This influence is achieved through three axes: (1) By displacement of potential pathogens via competitive exclusion; (2) by offering protection to the host through the secretion of various defensive mediators; and (3) by supplying the host with essential nutrients. We will analyze and discuss almost all the in vitro and in vivo studies of the past 2 years dealing with the possible favorable effects of certain probiotic genus on gut immunological responses, highlighting which species are the most beneficial against intestinal inflammation.
    Keywords:  Bifidobacteriaceae; Immune responses; Intestinal inflammation; Lactobacillaceae; Probiotics; Saccharomyces
    DOI:  https://doi.org/10.3748/wjg.v30.i15.2096
  28. Dev Comp Immunol. 2024 Apr 25. pii: S0145-305X(24)00060-0. [Epub ahead of print]157 105188
    Induction of trained immunity using β-glucan and its protective responses in Nile tilapia, Oreochromis niloticus.
    David Waikhom, Jeena Kezhedath, Sooraj Nediyirippil Suresh, Megha Kadam Bedekar, Tincy Varghese, Pani Prasad Kurcheti, Rajendran Kooloth Valappil.
      Emerging and re-emerging diseases in fish cause drastic economic losses in the aquaculture sector. To combat the impact of disease outbreaks and prevent the emergence of infections in culture systems, understanding the advanced strategies for protecting fish against infections is inevitable in fish health research. Therefore, the present study aimed to evaluate the induction of trained immunity and its protective efficacy against Streptococcus agalactiae in tilapia. For this, Nile tilapia and the Tilapia head kidney macrophage primary culture were primed using β-glucan @200 μg/10 g body weight and 10 μg/mL respectively. Expression profiles of the markers of trained immunity and production of metabolites were monitored at different time points, post-priming and training, which depicted enhanced responsiveness. Higher lactate and lactate dehydrogenase (LDH) production in vitro suggests heightened glycolysis induced by priming of the cells using β-glucan. A survival rate of 60% was observed in β-glucan trained fish post challenge with virulent S. agalactiae at an LD50 of 2.6 × 107 cfu/ml, providing valuable insights into promising strategies of trained immunity for combating infections in fish.
    Keywords:  Glucan; Innate immune memory; Nile tilapia; Streptococcus agalactiae; Trained immunity
    DOI:  https://doi.org/10.1016/j.dci.2024.105188
  29. Immunity. 2024 Apr 22. pii: S1074-7613(24)00208-5. [Epub ahead of print]
    CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment.
    Jingyun Luan, Cynthia Truong, Aleksandra Vuchkovska, Weijie Guo, Jennifer Good, Bijun Liu, Audrey Gang, Nicole Infarinato, Katherine Stewart, Lisa Polak, Hilda Amalia Pasolli, Emma Andretta, Alexander Y Rudensky, Elaine Fuchs, Yuxuan Miao.
      Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.
    Keywords:  CD80; Treg cell; hair follicle stem cell; neutrophils; wound repair
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.003
  30. Nat Rev Immunol. 2024 Apr 29.
    DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways.
    Yi Huang, Wei Jiang, Rongbin Zhou.
      Damage-associated molecular patterns (DAMPs) are endogenous molecules that are released from host cells as a result of cell death or damage. The release of DAMPs in tissues is associated with loss of tissue homeostasis. Sensing of DAMPs by innate immune receptors triggers inflammation, which can be beneficial in initiating the processes that restore tissue homeostasis but can also drive inflammatory diseases. In recent years, the sensing of intracellular DAMPs has received extensive attention in the field of sterile inflammation. However, emerging studies have shown that DAMPs that originate from neighbouring cells, and even from distal tissues or organs, also mediate sterile inflammatory responses. This multi-level sensing of DAMPs is crucial for intercellular, trans-tissue and trans-organ communication. Here, we summarize how DAMP-sensing receptors detect DAMPs from intracellular, intercellular or distal tissue and organ sources to mediate sterile inflammation. We also discuss the possibility of targeting DAMPs or their corresponding receptors to treat inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41577-024-01027-3
  31. Microbiol Spectr. 2024 Apr 30. e0351623
    An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection.
    Carly G K Ziegler, Anna H Owings, Michelle Galeas-Pena, Samuel W Kazer, Vincent N Miao, Andrew W Navia, Ying Tang, Joshua D Bromley, Peter Lotfy, Meredith Sloan, Hannah Laird, Haley B Williams, Micayla George, Riley S Drake, Yilianys Pride, George E Abraham, Michal Senitko, Tanya O Robinson, Gill Diamond, Michail S Lionakis, Alex K Shalek, Jose Ordovas-Montanes, Bruce H Horwitz, Sarah C Glover.
      Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection.IMPORTANCE: In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.
    Keywords:  COVID-19; Candida; IL17; SARS-CoV-2; anti-viral; cytokine; epithelial immunity; fungal infection; human; interferon; nasal mucosa; scRNA-seq
    DOI:  https://doi.org/10.1128/spectrum.03516-23
  32. Nature. 2024 May 01.
    Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.
    Brian Lin, Viral S Shah, Chaim Chernoff, Jiawei Sun, Gergana G Shipkovenska, Vladimir Vinarsky, Avinash Waghray, Jiajie Xu, Andrew D Leduc, Constantin A Hintschich, Manalee Vishnu Surve, Yanxin Xu, Diane E Capen, Jorge Villoria, Zhixun Dou, Lida P Hariri, Jayaraj Rajagopal.
      Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-024-07377-1
  33. Ecotoxicol Environ Saf. 2024 Apr 26. pii: S0147-6513(24)00433-0. [Epub ahead of print]277 116357
    Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.
    Jinming Zhang, Jiangzhou Du, Dongyu Liu, Jinzhong Zhuo, Lanhe Chu, Yanqun Li, Lin Gao, Mingming Xu, Weimou Chen, Wufeng Huang, Lingyan Xie, Junwei Chen, Xiaojing Meng, Fei Zou, Shaoxi Cai, Hangming Dong.
      Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.
    Keywords:  Alveolar epithelial cell; Ferroptosis; Polystyrene microplastics; Pulmonary fibrosis; cGAS/STING signaling
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116357
  34. Infect Dis Ther. 2024 May 03.
    Nasal Staphylococcus aureus Carriage and Antimicrobial Resistance Profiles Among Community-Dwelling Adults in Jiangsu, China.
    Wenjing Hu, Yang Wang, Lu Zhou, Kai Chu, Pengfei Jin, Qi Liang, Jingxin Li, Zhongming Tan, Fengcai Zhu.
      INTRODUCTION: Persistent nasal carriage has been associated with Staphylococcus aureus infection. Previous S. aureus studies in Asia have primarily focused on clinical patients, providing limited information on persistent nasal carriage among the general adult population.METHODS: This study examined 143 healthy adults in a community in Jiangsu, China. Nasal swab samples were collected 10 times. The colonization status was identified using SPA typing. We also determined antimicrobial susceptibility, genotype, and genomic characteristics of S. aureus.
    RESULTS: The prevalence of S. aureus nasal carriage among the community individuals was on average 16.78%. The carriage rates of methicillin-resistant S. aureus and multidrug-resistant S. aureus were 6.29% and 7.69%, respectively. We identified 8.39% persistent carriers, 39.16% intermittent carriers, and 52.45% noncarriers. Furthermore, family members displayed concordance in terms of genotype and genomic characteristics.
    CONCLUSION: Persistent nasal sampling captured intermittent carriers that were missed during short-term sampling, thus highlighting the necessity for regular community testing. SPA typing can serve as a rapid method for determining S. aureus colonization. The potential for intrafamilial transmission of S. aureus is evident, with persistent carriers being the most probable source of infection.
    Keywords:  Drug resistance; MLST; SPA; Whole genome sequencing
    DOI:  https://doi.org/10.1007/s40121-024-00969-4
  35. Sci Rep. 2024 04 27. 14(1): 9722
    S100a9 might act as a modulator of the Toll-like receptor 4 transduction pathway in chronic rhinosinusitis with nasal polyps.
    Nasibeh Khayer, Maryam Jalessi, Mohammad Farhadi, Zahra Azad.
      Chronic rhinosinusitis with nasal polyp (CRSwNP) is a highly prevalent disorder characterized by persistent nasal and sinus mucosa inflammation. Despite significant morbidity and decreased quality of life, there are limited effective treatment options for such a disease. Therefore, identifying causal genes and dysregulated pathways paves the way for novel therapeutic interventions. In the current study, a three-way interaction approach was used to detect dynamic co-expression interactions involved in CRSwNP. In this approach, the internal evolution of the co-expression relation between a pair of genes (X, Y) was captured under a change in the expression profile of a third gene (Z), named the switch gene. Subsequently, the biological relevancy of the statistically significant triplets was confirmed using both gene set enrichment analysis and gene regulatory network reconstruction. Finally, the importance of identified switch genes was confirmed using a random forest model. The results suggested four dysregulated pathways in CRSwNP, including "positive regulation of intracellular signal transduction", "arachidonic acid metabolic process", "spermatogenesis" and "negative regulation of cellular protein metabolic process". Additionally, the S100a9 as a switch gene together with the gene pair {Cd14, Tpd52l1} form a biologically relevant triplet. More specifically, we suggested that S100a9 might act as a potential upstream modulator in toll-like receptor 4 transduction pathway in the major CRSwNP pathologies.
    DOI:  https://doi.org/10.1038/s41598-024-60205-4
  36. Drug Des Devel Ther. 2024 ;18 1369-1384
    Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.
    Mengtian Shan, Huimin Wan, Linyu Ran, Jihui Ye, Wang Xie, Jingjing Lu, Xueping Hu, Shengjie Deng, Wenyu Zhang, Miao Chen, Feilong Wang, Zhongliang Guo.
      Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo.Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence.
    Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1β, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1β and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue.
    Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.
    Keywords:  NLRP3 inflammasome; acute lung injury; acute respiratory distress syndrome; dynasore; inflammation; pyroptosis
    DOI:  https://doi.org/10.2147/DDDT.S444408
  37. Nature. 2024 May 01.
    Dad's microbiome can affect offspring's health - in mice.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Astronomy and astrophysics; Cancer; Genomics; Molecular biology; Palaeontology
    DOI:  https://doi.org/10.1038/d41586-024-01313-z
  38. Microbiology (Reading). 2024 Apr;170(4):
    Exploiting cooperative pathogen behaviour for enhanced antibiotic potency: A Trojan horse approach.
    Alper Mutlu, Emily J Vanderpool, Kendra P Rumbaugh, Stephen P Diggle, Ashleigh S Griffin.
      Antimicrobial resistance poses an escalating global threat, rendering traditional drug development approaches increasingly ineffective. Thus, novel alternatives to antibiotic-based therapies are needed. Exploiting pathogen cooperation as a strategy for combating resistant infections has been proposed but lacks experimental validation. Empirical findings demonstrate the successful invasion of cooperating populations by non-cooperating cheats, effectively reducing virulence in vitro and in vivo. The idea of harnessing cooperative behaviours for therapeutic benefit involves exploitation of the invasive capabilities of cheats to drive medically beneficial traits into infecting populations of cells. In this study, we employed Pseudomonas aeruginosa quorum sensing cheats to drive antibiotic sensitivity into both in vitro and in vivo resistant populations. We demonstrated the successful invasion of cheats, followed by increased antibiotic effectiveness against cheat-invaded populations, thereby establishing an experimental proof of principle for the potential application of the Trojan strategy in fighting resistant infections.
    Keywords:  antimicrobial resistance; cheat; cooperation; microbial social evolution; quorum sensing; trojan cheat; virulence
    DOI:  https://doi.org/10.1099/mic.0.001454
  39. Front Immunol. 2024 ;15 1342497
    Myeloid-derived suppressor cells in influenza virus-induced asthma exacerbation.
    Chiel van Geffen, Tim Lange, Saeed Kolahian.
      Myeloid-derived suppressor cells (MDSCs) are a phenotypically heterogenous group of cells that potently suppress the immune response. A growing body of evidence supports the important role of MDSCs in a variety of lung diseases, such as asthma. However, the role of MDSCs in asthma exacerbation has so far not been investigated. Here, we studied the role of MDSCs in a murine model of influenza virus-induced asthma exacerbation. BALB/c mice were exposed to house dust mite (HDM) three times a week for a total of five weeks to induce a chronic asthmatic phenotype, which was exacerbated by additional exposure to the A/Hamburg/5/2009 hemagglutinin 1 neuraminidase 1 (H1N1) influenza virus. Induction of lung inflammatory features, production of T helper (Th) 1- and Th2- associated inflammatory cytokines in the lavage fluid and an increased airway hyper-responsiveness were observed, establishing the asthma exacerbation model. The number and activity of pulmonary M-MDSCs increased in exacerbated asthmatic mice compared to non-exacerbated asthmatic mice. Furthermore, depletion of MDSCs aggravated airway hyper-responsiveness in exacerbated asthmatic mice. These findings further denote the role of MDSCs in asthma and provide some of the first evidence supporting a potential important role of MDSCs in asthma exacerbation.
    Keywords:  asthma; asthma exacerbation; inflammation; influenza virus; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1342497
  40. Cell Rep. 2024 May 02. pii: S2211-1247(24)00498-4. [Epub ahead of print]43(5): 114170
    Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
    Jose A Martinez-Sarmiento, Maria Pia Cosma, Melike Lakadamyali.
      During cell fate transitions, cells remodel their transcriptome, chromatin, and epigenome; however, it has been difficult to determine the temporal dynamics and cause-effect relationship between these changes at the single-cell level. Here, we employ the heterokaryon-mediated reprogramming system as a single-cell model to dissect key temporal events during early stages of pluripotency conversion using super-resolution imaging. We reveal that, following heterokaryon formation, the somatic nucleus undergoes global chromatin decompaction and removal of repressive histone modifications H3K9me3 and H3K27me3 without acquisition of active modifications H3K4me3 and H3K9ac. The pluripotency gene OCT4 (POU5F1) shows nascent and mature RNA transcription within the first 24 h after cell fusion without requiring an initial open chromatin configuration at its locus. NANOG, conversely, has significant nascent RNA transcription only at 48 h after cell fusion but, strikingly, exhibits genomic reopening early on. These findings suggest that the temporal relationship between chromatin compaction and gene activation during cellular reprogramming is gene context dependent.
    Keywords:  CP: Molecular biology; CP: Stem cell research; Nanog; Oct4; cellular reprogramming; chromatin; pluripotency; single-molecule FISH; super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2024.114170
  41. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2313823121
    Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type-specific HIV latency reactivation.
    Alexandra Blanco, Robert A Coronado, Neha Arun, Kelly Ma, Roy D Dar, Collin Kieffer.
      HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, and function. To investigate these processes, we generated an HIV latency model in THP-1 monocytes and showed differential levels of HIV reactivation among clonal populations. Monocyte-to-macrophage differentiation of HIV-infected primary human CD14+ and THP-1 cells induced HIV reactivation and showed that virus production increased concomitant with macrophage differentiation. We applied the HIV-infected THP-1 monocyte-to-macrophage (MLat) model to assess the biological mechanisms regulating HIV latency dynamics during monocyte-to-macrophage differentiation. We pinpointed protein kinase C signaling pathway activation and Cyclin T1 upregulation as inherent differentiation mechanisms that regulate HIV latency reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 macrophages suppressed HIV reactivation while anti-inflammatory M2 macrophages promoted HIV reactivation. Because macrophages rely on reactive-oxygen species (ROS) to exert numerous cellular functions, we disrupted redox pathways and found that inhibitors of the thioredoxin (Trx) system acted as latency-promoting agents in T-cells and monocytes, but opposingly acted as latency-reversing agents in macrophages. We explored this mechanism with Auranofin, a clinical candidate for reducing HIV reservoirs, and demonstrated Trx reductase inhibition led to ROS induced NF-κB activity, which promoted HIV reactivation in macrophages, but not in T-cells and monocytes. Collectively, cell type-specific differences in HIV latency regulation could pose a barrier to HIV eradication strategies.
    Keywords:  HIV latency; latency-promoting agents; monocyte-derived macrophages; myeloid reservoir; thioredoxin
    DOI:  https://doi.org/10.1073/pnas.2313823121
  42. Nat Immunol. 2024 May;25(5): 741-742
    Baseline JAK-STAT signaling maintains immune cell homeostasis.
      
    DOI:  https://doi.org/10.1038/s41590-024-01805-0
  43. Animal Model Exp Med. 2024 May 02.
    The ever-changing microenvironment of Staphylococcus aureus in cutaneous infections.
    Zhenru Zhou, Jing Tian, Shi Li, Liyue Fei, Min Dai, Nana Long.
      BACKGROUND: Staphylococcus aureus is responsible for the majority of skin and soft tissue infections, which are often diagnosed at a late stage, thereby impacting treatment efficacy. Our study was designed to reveal the physiological changes at different stages of infection by S. aureus through the combined analysis of variations in the skin microenvironment, providing insights for the diagnosis and treatment of S. aureus infections.METHODS: We established a murine model of skin and soft tissue infection with S. aureus as the infectious agent to investigate the differences in the microenvironment at different stages of infection. By combining analysis of the host immune status and histological observations, we elucidate the progression of S. aureus infection in mice.
    RESULTS: The results indicate that the infection process in mice can be divided into at least two stages: early infection (1-3 days post-infection) and late infection (5-7 days post-infection). During the early stage of infection, notable symptoms such as erythema and abundant exudate at the infection site were observed. Histological examination revealed infiltration of numerous neutrophils and bacterial clusters, accompanied by elevated levels of cytokines (IL-6, IL-10). There was a decrease in microbial alpha diversity within the microenvironment (Shannon, Faith's PD, Chao1, Observed species, Simpson, Pielou's E). In contrast, during the late stage of infection, a reduction or even absence of exudate was observed at the infected site, accompanied by the formation of scabs. Additionally, there was evidence of fibroblast proliferation and neovascularization. The levels of cytokines and microbial composition gradually returned to a healthy state.
    CONCLUSION: This study reveals synchrony between microbial composition and histological/immunological changes during S. aureus-induced SSTIs.
    Keywords:   Staphylococcus aureus ; microbial composition; skin and soft tissue infection
    DOI:  https://doi.org/10.1002/ame2.12413
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