bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024‒01‒21
fifty-one papers selected by
Chun-Chi Chang, University Hospital Zurich
  1. Staphylococcus aureus senses human neutrophils via PerR to coordinate the expression of the toxin LukAB.
  2. Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.
  3. Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.
  4. Positioning the preventive potential of microbiome treatments for cystic fibrosis in the context of current therapies.
  5. Early-life airway microbiome and childhood asthma development.
  6. Can Therapeutic Targeting of the Human Microbiome Influence Asthma Management? A Pro/Con Debate.
  7. A bacterial sialidase mediates early-life colonization by a pioneering gut commensal.
  8. Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks.
  9. BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.
  10. Histidine transport is essential for the growth of Staphylococcus aureus at low pH.
  11. Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
  12. Iron, Copper, and Zinc Homeostasis in the Battle between Macrophage and Mycobacterium Tuberculosis.
  13. Exposure and resistance to lantibiotics impact microbiota composition and function.
  14. Infection prevention - How can we prevent community transmission of CO-MRSA?
  15. Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.
  16. Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β.
  17. O6-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK.
  18. Mycobacterium tuberculosis Antigen 85B modifies BCG-induced anti-tuberculosis immunity and favors pathogen survival.
  19. Microbes little helpers and suppliers for therapeutic asthma approaches.
  20. Implications of vaccine non-specific effects on licensure of new vaccines.
  21. Bridging tissue repair and epithelial carcinogenesis: epigenetic memory and field cancerization.
  22. Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption.
  23. Dynamics of macrophage polarization support Salmonella persistence in a whole living organism.
  24. Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.
  25. Complement in breast milk modifies offspring gut microbiota to promote infant health.
  26. Visualizing Macrophage Phenotypes and Polarization in Diseases: From Biomarkers to Molecular Probes.
  27. Metabolic waypoints during T cell differentiation.
  28. The biofilm proteome of Staphylococcus aureus and its implications for therapeutic interventions to biofilm-associated infections.
  29. Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
  30. Lung microbiome: new insights into the pathogenesis of respiratory diseases.
  31. To die or not to die: Gasdermins in intestinal health and disease.
  32. Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases⋆.
  33. Modulation of Designed Gut Bacterial Communities by Prebiotics and the Impact of Their Metabolites on Intestinal Cells.
  34. The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches.
  35. Gut-joint axis: Oral Probiotic ameliorates Osteoarthritis.
  36. Oral and rectal colonization of methicillin-resistant Staphylococcus aureus in long-term care facility residents and their association with clinical status.
  37. CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance and immune homeostasis.
  38. Looking Beyond the Lower Airways for Microbes Affecting Pulmonary Fibrosis.
  39. Atopic dermatitis: Pathophysiology, microbiota, and metabolome - A comprehensive review.
  40. Pyroptosis: a double-edged sword in lung cancer and other respiratory diseases.
  41. The Role of Neutrophil in COVID-19 - Positive or Negative.
  42. Ribosome Profiling Methods Adapted to the Study of RNA-Dependent Translation Regulation in Staphylococcus aureus.
  43. Epigenetic memory.
  44. Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori.
  45. Microbial evasion of the complement system: a continuous and evolving story.
  46. ANKRD22 aggravates sepsis-induced ARDS and promotes pulmonary M1 macrophage polarization.
  47. Yersiniabactin is a quorum-sensing autoinducer and siderophore in uropathogenic Escherichia coli.
  48. Vaginal Lactobacillus fatty acid response mechanisms reveal a novel strategy for bacterial vaginosis treatment.
  49. Tissue-resident macrophages exacerbate lung injury after remote sterile damage.
  50. Group A Streptococcus interactions with the host across time and space.
  51. Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis.
  1. Infect Immun. 2024 Jan 18. e0052623
    Staphylococcus aureus senses human neutrophils via PerR to coordinate the expression of the toxin LukAB.
    Avital Savin, Exene E Anderson, Sophie Dyzenhaus, Magdalena Podkowik, Bo Shopsin, Alejandro Pironti, Victor J Torres.
      Staphylococcus aureus is a gram-positive pathogen that poses a major health concern, in part due to its large array of virulence factors that allow infection and evasion of the immune system. One of these virulence factors is the bicomponent pore-forming leukocidin LukAB. The regulation of lukAB expression is not completely understood, especially in the presence of immune cells such as human polymorphonuclear neutrophils (hPMNs). Here, we screened for transcriptional regulators of lukAB during the infection of primary hPMNs. We uncovered that PerR, a peroxide sensor, is vital for hPMN-mediated induction of lukAB and that PerR upregulates cytotoxicity during the infection of hPMNs. Exposure of S. aureus to hydrogen peroxide (H2O2) alone also results in increased lukAB promoter activity, a phenotype dependent on PerR. Collectively, our data suggest that S. aureus uses PerR to sense the H2O2 produced by hPMNs to stimulate the expression of lukAB, allowing the bacteria to withstand these critical innate immune cells.IMPORTANCEStaphylococcus aureus utilizes a diverse set of virulence factors, such as leukocidins, to subvert human neutrophils, but how these toxins are regulated is incompletely defined. Here, we identified the peroxide-sensitive repressor, PerR, as a required protein involved in the induction of lukAB in the presence of primary human neutrophils, a phenotype directly linked to the ability of PerR to sense H2O2. Thus, we show that S. aureus coordinates sensing and resistance to oxidative stress with toxin production to promote pathogen survival.
    Keywords:  LukAB; MRSA; PerR; Staphylococcus aureus; cytotoxins; neutrophils; pore-forming toxins
    DOI:  https://doi.org/10.1128/iai.00526-23
  2. PLoS Pathog. 2024 Jan;20(1): e1011871
    Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.
    Dat Mai, Ana Jahn, Tara Murray, Michael Morikubo, Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Johannes Nemeth, Kevin Urdahl, Alan H Diercks, Alan Aderem, Alissa C Rothchild.
      Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.
    DOI:  https://doi.org/10.1371/journal.ppat.1011871
  3. PLoS Pathog. 2024 Jan;20(1): e1011918
    Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.
    Xiao-Qi Lin, Zhen-Zhen Liu, Cheng-Kai Zhou, Liang Zhang, Yu Gao, Xue-Yue Luo, Jian-Gang Zhang, Wei Chen, Yong-Jun Yang.
      Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.
    DOI:  https://doi.org/10.1371/journal.ppat.1011918
  4. Cell Rep Med. 2024 Jan 16. pii: S2666-3791(23)00600-6. [Epub ahead of print]5(1): 101371
    Positioning the preventive potential of microbiome treatments for cystic fibrosis in the context of current therapies.
    Eline Cauwenberghs, Ilke De Boeck, Irina Spacova, Ilke Van Tente, Joke Bastiaenssen, Elise Lammertyn, Stijn Verhulst, Kim Van Hoorenbeeck, Sarah Lebeer.
      Antibiotics and cystic fibrosis transmembrane conductance regulator (CFTR) modulators play a pivotal role in cystic fibrosis (CF) treatment, but both have limitations. Antibiotics are linked to antibiotic resistance and disruption of the airway microbiome, while CFTR modulators are not widely accessible, and structural lung damage and pathogen overgrowth still occur. Complementary strategies that can beneficially modulate the airway microbiome in a preventive way are highly needed. This could be mediated via oral probiotics, which have shown some improvement of lung function and reduction of airway infections and exacerbations, as a cost-effective approach. However, recent data suggest that specific and locally administered probiotics in the respiratory tract might be a more targeted approach to prevent pathogen outgrowth in the lower airways. This review aims to summarize the current knowledge on the CF airway microbiome and possibilities of microbiome treatments to prevent bacterial and/or viral infections and position them in the context of current CF therapies.
    Keywords:  cystic fibrosis; lactic acid bacteria; live biotherapeutics; microbiome; microbiome-based strategies; probiotics; respiratory tract
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101371
  5. Eur Respir J. 2024 Jan;pii: 2302187. [Epub ahead of print]63(1):
    Early-life airway microbiome and childhood asthma development.
    Zhaozhong Zhu.
      
    DOI:  https://doi.org/10.1183/13993003.02187-2023
  6. J Allergy Clin Immunol Pract. 2024 Jan 13. pii: S2213-2198(24)00061-8. [Epub ahead of print]
    Can Therapeutic Targeting of the Human Microbiome Influence Asthma Management? A Pro/Con Debate.
    Andrew L Kau, Anne L Rosen, Christian Rosas-Salazar.
      Asthma is a clinically heterogenous disease and despite substantial improvements in therapies, there remains an unmet need for well-tolerated, effective treatments. Observational studies have demonstrated that alterations in the respiratory and gut microbiome are associated with the development of asthma as well as its severity. These findings are supported by preclinical models demonstrating that respiratory and gut microbes can alter airway inflammation. Therapeutic approaches to target the human microbiome have been increasingly applied to a wide range of acute and chronic diseases, but there are currently no microbiome-based therapeutics approved for the treatment of asthma. This clinical commentary addresses the future role of microbiome-based therapeutics in asthma management from both a pro and con perspective. We examine (1) the prospects for clinical studies demonstrating a causal relationship between the human microbiome and the severity of asthma, (2) the challenges and potential solutions for designing, testing, and implementing a microbiome-based therapeutic, and (3) the possibility of microbiome-based therapeutics for conditions co-morbid to asthma. We conclude by identifying research priorities that will help determine the future of microbiome-based therapeutics for the management of asthma.
    Keywords:  Asthma; microbiome; probiotics; therapeutics
    DOI:  https://doi.org/10.1016/j.jaip.2023.12.053
  7. Cell Host Microbe. 2024 Jan 09. pii: S1931-3128(23)00509-7. [Epub ahead of print]
    A bacterial sialidase mediates early-life colonization by a pioneering gut commensal.
    Ekaterina Buzun, Chia-Yun Hsu, Kristija Sejane, Renee E Oles, Adriana Vasquez Ayala, Luke R Loomis, Jiaqi Zhao, Leigh-Ana Rossitto, Dominic M McGrosso, David J Gonzalez, Lars Bode, Hiutung Chu.
      The early microbial colonization of the gastrointestinal tract can have long-term impacts on development and health. Keystone species, including Bacteroides spp., are prominent in early life and play crucial roles in maintaining the structure of the intestinal ecosystem. However, the process by which a resilient community is curated during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa in early life and regulates a commensal colonization program. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. NanH is required for vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and microbiota mediated through host-derived glycans to promote stable colonization.
    Keywords:  commensal colonization; early-life microbiome; host-microbe interactions; human milk oligosaccharides
    DOI:  https://doi.org/10.1016/j.chom.2023.12.014
  8. Sci Rep. 2024 01 17. 14(1): 1454
    Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks.
    Quen J Cheng, Kylie Farrell, Jeffrey Fenn, Zuchao Ma, Sara K Makanani, Jonathan Siemsen.
      Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many Dectin-1 ligands exist, and it is not known whether these all produce the same phenotype. Using a well-established in vitro model of innate immune training, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of cytokines such as TNF and IL-6. Zymosan activated NFκB and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1 ligands.
    DOI:  https://doi.org/10.1038/s41598-024-51620-8
  9. Nat Immunol. 2024 Jan 15.
    BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.
    Kim A Tran, Erwan Pernet, Mina Sadeghi, Jeffrey Downey, Julia Chronopoulos, Elizabeth Lapshina, Oscar Tsai, Eva Kaufmann, Jun Ding, Maziar Divangahi.
      After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αβ T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.
    DOI:  https://doi.org/10.1038/s41590-023-01739-z
  10. PLoS Pathog. 2024 Jan 16. 20(1): e1011927
    Histidine transport is essential for the growth of Staphylococcus aureus at low pH.
    Catrin M Beetham, Christopher F Schuster, Igor Kviatkovski, Marina Santiago, Suzanne Walker, Angelika Gründling.
      Staphylococcus aureus is an opportunistic pathogen capable of causing many different human diseases. During colonization and infection, S. aureus will encounter a range of hostile environments, including acidic conditions such as those found on the skin and within macrophages. However, little is known about the mechanisms that S. aureus uses to detect and respond to low pH. Here, we employed a transposon sequencing approach to determine on a genome-wide level the genes required or detrimental for growth at low pH. We identified 31 genes that were essential for the growth of S. aureus at pH 4.5 and confirmed the importance of many of them through follow up experiments using mutant strains inactivated for individual genes. Most of the genes identified code for proteins with functions in cell wall assembly and maintenance. These data suggest that the cell wall has a more important role than previously appreciated in promoting bacterial survival when under acid stress. We also identified several novel processes previously not linked to the acid stress response in S. aureus. These include aerobic respiration and histidine transport, the latter by showing that one of the most important genes, SAUSA300_0846, codes for a previously uncharacterized histidine transporter. We further show that under acid stress, the expression of the histidine transporter gene is increased in WT S. aureus. In a S. aureus SAUSA300_0846 mutant strain expression of the histidine biosynthesis genes is induced under acid stress conditions allowing the bacteria to maintain cytosolic histidine levels. This strain is, however, unable to maintain its cytosolic pH to the same extent as a WT strain, revealing an important function specifically for histidine transport in the acid stress response of S. aureus.
    DOI:  https://doi.org/10.1371/journal.ppat.1011927
  11. J Clin Invest. 2024 Jan 16. pii: e175445. [Epub ahead of print]134(2):
    Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
    Corey Dussold, Kaylee Zilinger, Jillyn Turunen, Amy B Heimberger, Jason Miska.
      Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.
    DOI:  https://doi.org/10.1172/JCI175445
  12. Curr Med Chem. 2024 Jan 12.
    Iron, Copper, and Zinc Homeostasis in the Battle between Macrophage and Mycobacterium Tuberculosis.
    Zisha Yang, Li Zhang, Yan Wang, Jiang Pi, Duo Peng, Yunhong Yao, Junfa Xu, Yi Zhao.
      Iron, copper, and zinc play integral roles in the battle against Mycobacterium tuberculosis (Mtb) infection; however, they are often trapped between nutrients and toxins, posing a significant challenge to macrophages and Mtb to utilize them. Due to this two-sided effect, macrophages and Mtb strictly regulate metal uptake, storage, and excretion. This review discusses the balanced regulation of iron, copper, and zinc in macrophages and Mtb during infection, focusing on the intracellular metal regulatory system. Macrophages typically use the two-sided effect of metals to limit Mtb access to nutrients or poison them. Mtb has developed a metal metabolism regulatory mechanism compatible with the nutritional immune strategy. This includes the mediation of relevant metalloproteins and metalloenzymes to maintain the multimetal balance. This review also explored the regulation of metal metabolism homeostasis in macrophages resistant to Mtb infection, providing a theoretical foundation for identifying potential clinical targets for Mtb infection, developing metalloid anti-tuberculosis drugs, and understanding the immune mechanisms against intracellular Mtb infection.
    Keywords:  Mycobacterium tuberculosis; copper; iron; macrophage.; metal ion homeostasis; zinc
    DOI:  https://doi.org/10.2174/0109298673283407231225140659
  13. bioRxiv. 2023 Dec 30. pii: 2023.12.30.573728. [Epub ahead of print]
    Exposure and resistance to lantibiotics impact microbiota composition and function.
    Zhenrun J Zhang, Cody Cole, Huaiying Lin, Chunyu Wu, Fidel Haro, Emma McSpadden, Wilfred A van der Donk, Eric G Pamer.
      The intestinal microbiota is composed of hundreds of distinct microbial species that interact with each other and their mammalian host. Antibiotic exposure dramatically impacts microbiota compositions and leads to acquisition of antibiotic-resistance genes. Lantibiotics are ribosomally synthesized and post-translationally modified peptides produced by some bacterial strains to inhibit the growth of competing bacteria. Nisin A is a lantibiotic produced by Lactococcus lactis that is commonly added to food products to reduce contamination with Gram-positive pathogens. Little is known, however, about lantibiotic-resistance of commensal bacteria inhabiting the human intestine. Herein, we demonstrate that Nisin A administration to mice alters fecal microbiome compositions and the concentration of taurine-conjugated primary bile acids. Lantibiotic Resistance System genes (LRS) are encoded by lantibiotic-producing bacterial strains but, we show, are also prevalent in microbiomes across human cohorts spanning vastly different lifestyles and 5 continents. Bacterial strains encoding LRS have enhanced in vivo fitness upon dietary exposure to Nisin A but reduced fitness in the absence of lantibiotic pressure. Differential binding of host derived, secreted IgA contributes to fitness discordance between bacterial strains encoding or lacking LRS. Although LRS are associated with mobile genetic elements, sequence comparisons of LRS encoded by distinct bacterial species suggest they have been long-term components of their respective genomes. Our study reveals the prevalence, abundance and physiologic significance of an underappreciated subset of antimicrobial resistance genes encoded by commensal bacterial species constituting the human gut microbiome, and provides insights that will guide development of microbiome augmenting strategies.
    DOI:  https://doi.org/10.1101/2023.12.30.573728
  14. Clin Microbiol Infect. 2024 Jan 11. pii: S1198-743X(24)00010-7. [Epub ahead of print]
    Infection prevention - How can we prevent community transmission of CO-MRSA?
    Carol M Kao, Stephanie A Fritz.
      BACKGROUND: Staphylococcus aureus is a versatile organism, capable of existing as a commensal organism while also possessing pathogenic potential. The emergence of clinically and genetically distinct strains of methicillin-resistant S. aureus (MRSA), termed community-onset MRSA (CO-MRSA), resulted in an epidemic of invasive and skin and soft tissue infections (SSTI) in otherwise healthy individuals without traditional risk factors. Colonization with S. aureus is a risk factor for developing infection and also a source of transmission to close contacts. Outbreaks of S. aureus SSTI have been described in crowded settings and within households. Thus, preventive strategies are essential to interrupt recurrent infections.OBJECTIVES: The objective of this narrative review is to provide a comprehensive, evidence-based approach to prevent transmission of CO-MRSA. We highlight key clinical trials that emphasize the importance of household and environmental S. aureus colonization in propagating household transmission. Finally, we highlight research priorities to prevent S. aureus infection.
    SOURCES: We cite primary literature from peer-reviewed publications as sources for this review.
    CONTENT: Our recommended approach to the management of individuals presenting with skin abscesses includes optimal treatment of the initial infection and hygiene education. Decolonization measures should be recommended for individuals with recurrent SSTIs or whose household members have SSTIs. Targeted decolonization with topical antimicrobials should be prescribed to all affected individuals within the household.
    IMPLICATIONS: S. aureus infections result in substantial mortality and morbidity due to the high incidence of recurrent skin infections. While current decolonization strategies are beneficial, interventions are often costly to families and effectiveness wanes over time. Results from a recently completed trial evaluating integrated periodic decolonization and household environmental hygiene will further add to our understanding of what constitutes a sustainable decolonization approach. In addition, novel preventative strategies are being developed such as S. aureus vaccines, lytic agents, probiotics, microbiota transplants, and phage therapy.
    DOI:  https://doi.org/10.1016/j.cmi.2024.01.004
  15. JCI Insight. 2024 Jan 16. pii: e170316. [Epub ahead of print]
    Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus.
    S Marina Casalino-Matsuda, Fei Chen, Francisco J Gonzalez-Gonzalez, Hiroaki Matsuda, Aisha Nair, Hiam Abdala-Valencia, G R Scott Budinger, Jin-Tang Dong, Greg J Beitel, Peter Hs Sporn.
      Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMØs). We also show that zinc finger homeobox 3 (Zfhx3), a mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila, is expressed in mouse and human macrophages. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMØs and decreased viral replication, inflammatory lung injury and mortality in hypercapnic mice infected with influenza A virus. Our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease.
    Keywords:  Immunology; Influenza; Innate immunity; Macrophages; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.170316
  16. PLoS Biol. 2024 Jan 18. 22(1): e3002486
    Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β.
    Mor Zigdon, Jasmin Sawaed, Lilach Zelik, Dana Binyamin, Shira Ben-Simon, Nofar Asulin, Rachel Levin, Sonia Modilevsky, Maria Naama, Shahar Telpaz, Elad Rubin, Aya Awad, Wisal Sawaed, Sarina Harshuk-Shabso, Meital Nuriel-Ohayon, Mathumathi Krishnamohan, Michal Werbner, Omry Koren, Sebastian E Winter, Ron N Apte, Elena Voronov, Shai Bel.
      Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.
    DOI:  https://doi.org/10.1371/journal.pbio.3002486
  17. iScience. 2024 Jan 19. 27(1): 108733
    O6-methylguanine DNA methyltransferase regulates β-glucan-induced trained immunity of macrophages via farnesoid X receptor and AMPK.
    Salisa Benjaskulluecha, Atsadang Boonmee, MdFazlul Haque, Benjawan Wongprom, Thitiporn Pattarakankul, Chitsuda Pongma, Kittitach Sri-Ngern-Ngam, Pornlapat Keawvilai, Thadaphong Sukdee, Benjawan Saechue, Patipark Kueanjinda, Tanapat Palaga.
      Trained immunity is the heightened state of innate immune memory that enhances immune response resulting in nonspecific protection. Epigenetic changes and metabolic reprogramming are critical steps that regulate trained immunity. In this study, we reported the involvement of O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme of lesion induced by alkylating agents, in regulation the trained immunity induced by β-glucan (BG). Pharmacological inhibition or silencing of MGMT expression altered LPS stimulated pro-inflammatory cytokine productions in BG-trained bone marrow derived macrophages (BMMs). Targeted deletion of Mgmt in BMMs resulted in reduction of the trained responses both in vitro and in vivo models. The transcriptomic analysis revealed that the dampening trained immunity in MGMT KO BMMs is partially mediated by ATM/FXR/AMPK axis affecting the MAPK/mTOR/HIF1α pathways and the reduction in glycolysis function. Taken together, a failure to resolve a DNA damage may have consequences for innate immune memory.
    Keywords:  Cell biology; Immunology; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108733
  18. J Leukoc Biol. 2024 Jan 18. pii: qiae014. [Epub ahead of print]
    Mycobacterium tuberculosis Antigen 85B modifies BCG-induced anti-tuberculosis immunity and favors pathogen survival.
    Giovanni Piccaro, Gabriella Aquino, Vincenzo Gigantino, Valentina Tirelli, Massimo Sanchez, Egidio Iorio, Giuseppe Matarese, Antonio Cassone, Carla Palma.
      Tuberculosis is one of the deadliest infectious diseases worldwide. Mycobacterium tuberculosis (Mtb) has developed strategies not only to evade from host immunity but also to manipulate it for its survival. We investigated whether Mtb exploited the immunogenicity of Ag85B, one of its major secretory proteins, to redirect host anti-TB immunity to its advantage. We found that administration of Ag85B protein to mice vaccinated with Bacillus Calmette-Guérin (BCG) impaired the protection elicited by vaccination causing a more severe infection when mice were challenged with Mtb. Ag85B administration reduced BCG-induced CD4 T cell activation and IFN-γ, CCL-4 and IL-22 production in response to Mtb-infected cells. On the other hand, it promoted robust Ag85B-responsive IFN-γ-producing CD4 T cells, expansion of a subset of IFN-γ/IL-10-producing CD4+FOXP3+Treg cells, differential activation of IL-17/IL-22 responses and activation of regulatory and exhaustion pathways, including programmed death-ligand 1 expression on macrophages. All this resulted in impaired intracellular Mtb growth control by systemic immunity, both at pre- and post-Mtb challenge. Interestingly, Mtb infection itself generated Ag85B-reactive inflammatory immune cells incapable of clearing Mtb in both unvaccinated and BCG-vaccinated mice. Our data suggest that Mtb can exploit the strong immunogenicity of Ag85B to promote its own survival and spread. Since Ag85B is normally secreted by replicating bacteria and it is commonly found in the lungs of the Mtb-infected host, our findings may advance the understanding on the mechanisms of Mtb pathogenesis and immune evasion.
    Keywords:  BCG; CD4 T cells; IFN-γ; antigen85B; intracellular M. tuberculosis killing; tuberculosis
    DOI:  https://doi.org/10.1093/jleuko/qiae014
  19. Respir Res. 2024 Jan 13. 25(1): 29
    Microbes little helpers and suppliers for therapeutic asthma approaches.
    Sebastian Reuter, Jonas Raspe, Christian Taube.
      Bronchial asthma is a prevalent and increasingly chronic inflammatory lung disease affecting over 300 million people globally. Initially considered an allergic disorder driven by mast cells and eosinophils, asthma is now recognized as a complex syndrome with various clinical phenotypes and immunological endotypes. These encompass type 2 inflammatory endotypes characterized by interleukin (IL)-4, IL-5, and IL-13 dominance, alongside others featuring mixed or non-eosinophilic inflammation. Therapeutic success varies significantly based on asthma phenotypes, with inhaled corticosteroids and beta-2 agonists effective for milder forms, but limited in severe cases. Novel antibody-based therapies have shown promise, primarily for severe allergic and type 2-high asthma. To address this gap, novel treatment strategies are essential for better control of asthma pathology, prevention, and exacerbation reduction. One promising approach involves stimulating endogenous anti-inflammatory responses through regulatory T cells (Tregs). Tregs play a vital role in maintaining immune homeostasis, preventing autoimmunity, and mitigating excessive inflammation after pathogenic encounters. Tregs have demonstrated their ability to control both type 2-high and type 2-low inflammation in murine models and dampen human cell-dependent allergic airway inflammation. Furthermore, microbes, typically associated with disease development, have shown immune-dampening properties that could be harnessed for therapeutic benefits. Both commensal microbiota and pathogenic microbes have demonstrated potential in bacterial-host interactions for therapeutic purposes. This review explores microbe-associated approaches as potential treatments for inflammatory diseases, shedding light on current and future therapeutics.
    Keywords:  Asthma; Gut–lung axis; Inflammation; Microbiome; Therapy; Treatment
    DOI:  https://doi.org/10.1186/s12931-023-02660-7
  20. Vaccine. 2024 Jan 18. pii: S0264-410X(24)00060-4. [Epub ahead of print]
    Implications of vaccine non-specific effects on licensure of new vaccines.
    Grant Munkwase.
      Immune memory was for a long time thought to be an exclusive feature of the adaptive immune system. Emerging evidence has shown that the innate immune system may exhibit memory which has been termed as trained immunity or innate immune memory. Trained immunity following vaccination may produce non-specific effects leading to reduction in morbidity and mortality from heterologous pathogens. This review looked at trained immunity as a mechanism for vaccine induced non-specific effects, mechanisms underlying trained immunity and known vaccine non-specific effects. A discussion is also made on the implications these vaccine non-specific effects may have on overall risk-benefit ratio evaluation by National Medicines Regulatory Authorities (NMRAs) during licensure of new vaccines. Epigenetic remodeling and "rewiring" of cellular metabolism in the innate immune cells especially monocytes, macrophages, and Natural Killer (NK) cells have been suggested to be the mechanisms underlying trained immunity. Trained immunity in other innate cells has largely remained elusive up to date. Non-specific effects have been extensively documented with Bacille Calmette-Guerin (BCG), measles vaccine and oral polio vaccine but it remains unclear if other vaccines may exhibit similar effects. All known vaccine non-specific effects have come from observations in epidemiological studies conducted post-vaccine licensure and roll out in target populations. It remains to be seen if early identification of non-specific effects especially those with protective benefits during the clinical development of new vaccines may contribute to the overall risk-benefit ratio evaluation during licensure by NMRAs.
    Keywords:  Implications; Licensure; Off-target effects; Risk–benefit ratio; Trained immunity mechanisms; Vaccine non-specific effects
    DOI:  https://doi.org/10.1016/j.vaccine.2024.01.048
  21. Cell Death Differ. 2024 Jan 16.
    Bridging tissue repair and epithelial carcinogenesis: epigenetic memory and field cancerization.
    Chiara Levra Levron, Luca Elettrico, Carlotta Duval, Gabriele Piacenti, Valentina Proserpio, Giacomo Donati.
      The epigenome coordinates spatial-temporal specific gene expression during development and in adulthood, for the maintenance of homeostasis and upon tissue repair. The upheaval of the epigenetic landscape is a key event in the onset of many pathologies including tumours, where epigenetic changes cooperate with genetic aberrations to establish the neoplastic phenotype and to drive cell plasticity during its evolution. DNA methylation, histone modifiers and readers or other chromatin components are indeed often altered in cancers, such as carcinomas that develop in epithelia. Lining the surfaces and the cavities of our body and acting as a barrier from the environment, epithelia are frequently subjected to acute or chronic tissue damages, such as mechanical injuries or inflammatory episodes. These events can activate plasticity mechanisms, with a deep impact on cells' epigenome. Despite being very effective, tissue repair mechanisms are closely associated with tumour onset. Here we review the similarities between tissue repair and carcinogenesis, with a special focus on the epigenetic mechanisms activated by cells during repair and opted by carcinoma cells in multiple epithelia. Moreover, we discuss the recent findings on inflammatory and wound memory in epithelia and describe the epigenetic modifications that characterise them. Finally, as wound memory in epithelial cells promotes carcinogenesis, we highlight how it represents an early step for the establishment of field cancerization.
    DOI:  https://doi.org/10.1038/s41418-023-01254-6
  22. Sci Transl Med. 2024 Jan 17. 16(730): eadi9711
    Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption.
    Shakti K Bhattarai, Muxue Du, Abigail L Zeamer, Benedikt M Morzfeld, Tasia D Kellogg, Kaya Firat, Anna Benjamin, James M Bean, Matthew Zimmerman, Gertrude Mardi, Stalz Charles Vilbrun, Kathleen F Walsh, Daniel W Fitzgerald, Michael S Glickman, Vanni Bucci.
      Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of Mycobacterium tuberculosis, the world's most common infection, represents the longest antimicrobial exposure in humans. Here, we investigate gut microbiome dynamics over 20 months of multidrug-resistant tuberculosis (TB) and 6 months of drug-sensitive TB treatment in humans. We find that gut microbiome dynamics and TB clearance are shared predictive cofactors of the resolution of TB-driven inflammation. The initial severe taxonomic and functional microbiome disruption, pathobiont domination, and enhancement of antibiotic resistance that initially accompanied long-term antibiotics were countered by later recovery of commensals. This resilience was driven by the competing evolution of antimicrobial resistance mutations in pathobionts and commensals, with commensal strains with resistance mutations reestablishing dominance. Fecal-microbiota transplantation of the antibiotic-resistant commensal microbiome in mice recapitulated resistance to further antibiotic disruption. These findings demonstrate that antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials and identify microbiome dynamics as a predictor of disease resolution in antibiotic therapy of a chronic infection.
    DOI:  https://doi.org/10.1126/scitranslmed.adi9711
  23. Elife. 2024 Jan 15. pii: e89828. [Epub ahead of print]13
    Dynamics of macrophage polarization support Salmonella persistence in a whole living organism.
    Jade Leiba, Tamara Sipka, Christina Begon-Pescia, Matteo Bernardello, Sofiane Tairi, Lionello Bossi, Anne-Alicia Gonzalez, Xavier Mialhe, Emilio Gualda, Pablo Loza-Alvarez, Anne Blanc-Potard, Georges Lutfalla, Mai E Nguyen-Chi.
      Numerous intracellular bacterial pathogens interfere with macrophage function, including macrophage polarization, to establish a niche and persist. However, the spatiotemporal dynamics of macrophage polarization during infection within host remain to be investigated. Here, we implement a model of persistent Salmonella Typhimurium infection in zebrafish, which allows visualization of polarized macrophages and bacteria in real time at high-resolution. While macrophages polarize toward M1-like phenotype to control early infection, during later stages, Salmonella persists inside non-inflammatory clustered macrophages. Transcriptomic profiling of macrophages showed a highly dynamic signature during infection characterized by a switch from pro-inflammatory to anti-inflammatory/pro-regenerative status and revealed a shift in adhesion program. In agreement with this specific adhesion signature, macrophage trajectory tracking identifies motionless macrophages as a permissive niche for persistent Salmonella. Our results demonstrate that zebrafish model provides a unique platform to explore, in a whole organism, the versatile nature of macrophage functional programs during bacterial acute and persistent infections.
    Keywords:  infectious disease; microbiology; zebrafish
    DOI:  https://doi.org/10.7554/eLife.89828
  24. Nat Microbiol. 2024 Jan 16.
    Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.
    Hackwon Do, Zhong-Rui Li, Praveen Kumar Tripathi, Sonali Mitra, Stephanie Guerra, Ananya Dash, Dulanthi Weerasekera, Nishanth Makthal, Syed Shams, Shifu Aggarwal, Bharat Bhushan Singh, Di Gu, Yongle Du, Randall J Olsen, Christopher LaRock, Wenjun Zhang, Muthiah Kumaraswami.
      Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.
    DOI:  https://doi.org/10.1038/s41564-023-01583-9
  25. Cell. 2024 Jan 10. pii: S0092-8674(23)01384-3. [Epub ahead of print]
    Complement in breast milk modifies offspring gut microbiota to promote infant health.
    Dongqing Xu, Siyu Zhou, Yue Liu, Alan L Scott, Jian Yang, Fengyi Wan.
      Breastfeeding offers demonstrable benefits to newborns and infants by providing nourishment and immune protection and by shaping the gut commensal microbiota. Although it has been appreciated for decades that breast milk contains complement components, the physiological relevance of complement in breast milk remains undefined. Here, we demonstrate that weanling mice fostered by complement-deficient dams rapidly succumb when exposed to murine pathogen Citrobacter rodentium (CR), whereas pups fostered on complement-containing milk complement components in breast milk were shown to directly lyse specific members of gram-positive gut commensal microbiota via a C1-dependent, antibody-independent mechanism, resulting in the deposition of the membrane attack complex and subsequent bacterial lysis. By selectively eliminating members of the commensal gut community, complement components from breast milk shape neonate and infant gut microbial composition to be protective against environmental pathogens such as CR.
    Keywords:  Citrobacter rodentium; MAC deposition; Staphylococcus lentus; antibody-independent; infant health
    DOI:  https://doi.org/10.1016/j.cell.2023.12.019
  26. Phenomics. 2023 Dec;3(6): 613-638
    Visualizing Macrophage Phenotypes and Polarization in Diseases: From Biomarkers to Molecular Probes.
    Dan Ni, Heqing Zhou, Pengwei Wang, Fulin Xu, Cong Li.
      Macrophage is a kind of immune cell and performs multiple functions including pathogen phagocytosis, antigen presentation and tissue remodeling. To fulfill their functionally distinct roles, macrophages undergo polarization towards a spectrum of phenotypes, particularly the classically activated (M1) and alternatively activated (M2) subtypes. However, the binary M1/M2 phenotype fails to capture the complexity of macrophages subpopulations in vivo. Hence, it is crucial to employ spatiotemporal imaging techniques to visualize macrophage phenotypes and polarization, enabling the monitoring of disease progression and assessment of therapeutic responses to drug candidates. This review begins by discussing the origin, function and diversity of macrophage under physiological and pathological conditions. Subsequently, we summarize the identified macrophage phenotypes and their specific biomarkers. In addition, we present the imaging probes locating the lesions by visualizing macrophages with specific phenotype in vivo. Finally, we discuss the challenges and prospects associated with monitoring immune microenvironment and disease progression through imaging of macrophage phenotypes.
    Keywords:  Macrophage biomarkers; Macrophage phenotypes; Metabolic reprogramming; Molecular probes
    DOI:  https://doi.org/10.1007/s43657-023-00129-7
  27. Nat Immunol. 2024 Jan 18.
    Metabolic waypoints during T cell differentiation.
    Drew Wilfahrt, Greg M Delgoffe.
      This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor-major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process. Firstly, metabolites act as signal propagators that aid in the transmission of core activation signals, such as specific lipid species that are crucial at the immune synapse. Secondly, metabolites also function as unique signals that influence immune differentiation pathways, such as amino acid-induced mTORC1 signaling. Metabolites also play a substantial role in epigenetic remodeling, by directly modifying histones, altering gene expression and influencing T cell behavior. This Review discusses how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites. We underscore the integration of immunological and metabolic inputs in T cell function and suggest that metabolite availability is a fundamental determinant of adaptive immune responses.
    DOI:  https://doi.org/10.1038/s41590-023-01733-5
  28. Adv Protein Chem Struct Biol. 2024 ;pii: S1876-1623(23)00079-2. [Epub ahead of print]138 327-400
    The biofilm proteome of Staphylococcus aureus and its implications for therapeutic interventions to biofilm-associated infections.
    Dileep Francis, Gopika Veeramanickathadathil Hari, Abhijith Koonthanmala Subash, Anusha Bhairaddy, Atheene Joy.
      Staphylococcus aureus is a major healthcare concern due to its ability to inflict life-threatening infections and evolve antibiotic resistance at an alarming pace. It is frequently associated with hospital-acquired infections, especially device-associated infections. Systemic infections due to S. aureus are difficult to treat and are associated with significant mortality and morbidity. The situation is worsened by the ability of S. aureus to form social associations called biofilms. Biofilms embed a community of cells with the ability to communicate with each other and share resources within a polysaccharide or protein matrix. S. aureus establish biofilms on tissues and conditioned abiotic surfaces. Biofilms are hyper-tolerant to antibiotics and help evade host immune responses. Biofilms exacerbate the severity and recalcitrance of device-associated infections. The development of a biofilm involves various biomolecules, such as polysaccharides, proteins and nucleic acids, contributing to different structural and functional roles. Interconnected signaling pathways and regulatory molecules modulate the expression of these molecules. A comprehensive understanding of the molecular biology of biofilm development would help to devise effective anti-biofilm therapeutics. Although bactericidal agents, antimicrobial peptides, bacteriophages and nano-conjugated anti-biofilm agents have been employed with varying levels of success, there is still a requirement for effective and clinically viable anti-biofilm therapeutics. Proteins that are expressed and utilized during biofilm formation, constituting the biofilm proteome, are a particularly attractive target for anti-biofilm strategies. The proteome can be explored to identify potential anti-biofilm drug targets and utilized for rational drug discovery. With the aim of uncovering the biofilm proteome, this chapter explores the mechanism of biofilm formation and its regulation. Furthermore, it explores the antibiofilm therapeutics targeted against the biofilm proteome.
    Keywords:  Anti-biofilm agents; Biofilm proteome; Device-associated infections; PIA-dependent biofilms; PIA-independent biofilms; Quorum sensing; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.08.002
  29. PeerJ. 2024 ;12 e16825
    Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
    Hua Cheng, Yongbin Zheng.
      Macrophages and T cells in the tumor microenvironment (TME) play an important role in tumorigenesis and progression. However, TME is also characterized by metabolic reprogramming, which may affect macrophage and metabolic activity of T cells and promote tumor escape. Immunotherapy is an approach to fight tumors by stimulating the immune system in the host, but requires support and modulation of cellular metabolism. In this process, the metabolic roles of macrophages and T cells become increasingly important, and their metabolic status and interactions play a critical role in the success of immunotherapy. Therefore, understanding the metabolic state of T cells and macrophages in the TME and the impact of metabolic reprogramming on tumor therapy will help optimize subsequent immunotherapy strategies.
    Keywords:  Immunotherapy; Macrophages; Metabolic reprogramming; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.7717/peerj.16825
  30. Signal Transduct Target Ther. 2024 Jan 17. 9(1): 19
    Lung microbiome: new insights into the pathogenesis of respiratory diseases.
    Ruomeng Li, Jing Li, Xikun Zhou.
      The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community. The microbiome of healthy lungs is mainly derived from the upper respiratory tract (URT) microbiome but also has its own characteristic flora. The selection mechanisms in the lung, including clearance by coughing, pulmonary macrophages, the oscillation of respiratory cilia, and bacterial inhibition by alveolar surfactant, keep the microbiome transient and mobile, which is different from the microbiome in other organs. The pulmonary bacteriome has been intensively studied recently, but relatively little research has focused on the mycobiome and virome. This up-to-date review retrospectively summarizes the lung microbiome's history, composition, and function. We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses. More importantly, we focus on multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), fibrosis, bronchiectasis, and pneumonia. The impact of the lung microbiome on coronavirus disease 2019 (COVID-19) and lung cancer has also been comprehensively studied. Furthermore, by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field, we propose an outlook of the direction of lung microbiome research.
    DOI:  https://doi.org/10.1038/s41392-023-01722-y
  31. Semin Immunol. 2024 Jan 16. pii: S1044-5323(24)00003-4. [Epub ahead of print]71 101865
    To die or not to die: Gasdermins in intestinal health and disease.
    Zhaoyu Lin, Qianyue Chen, Hai-Bin Ruan.
      Intestinal homeostasis is achieved by the balance among intestinal epithelium, immune cells, and gut microbiota. Gasdermins (GSDMs), a family of membrane pore forming proteins, can trigger rapid inflammatory cell death in the gut, mainly pyroptosis and NETosis. Importantly, there is increasing literature on the non-cell lytic roles of GSDMs in intestinal homeostasis and disease. While GSDMA is low and PJVK is not expressed in the gut, high GSDMB and GSDMC expression is found almost restrictively in intestinal epithelial cells. Conversely, GSDMD and GSDME show more ubiquitous expression among various cell types in the gut. The N-terminal region of GSDMs can be liberated for pore formation by an array of proteases in response to pathogen- and danger-associated signals, but it is not fully understood what cell type-specific mechanisms activate intestinal GSDMs. The host relies on GSDMs for pathogen defense, tissue tolerance, and cancerous cell death; however, pro-inflammatory milieu caused by pyroptosis and excessive cytokine release may favor the development and progression of inflammatory bowel disease and cancer. Therefore, a thorough understanding of spatiotemporal mechanisms that control gasdermin expression, activation, and function is essential for the development of future therapeutics for intestinal disorders.
    Keywords:  GSDM; Immune cells; Inflammatory bowel disease; Intestinal epithelial cells; Pyroptosis
    DOI:  https://doi.org/10.1016/j.smim.2024.101865
  32. Liver Res. 2023 Jun;7(2): 116-123
    Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases⋆.
    Muhammad Umair Ijaz, Farzam Vaziri, Yu-Jui Yvonne Wan.
      Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.
    Keywords:  Bacillus Calmette-Guérin (BCG); Diabetes; Gut microbiota; Liver disease; Metabolic diseases; Trained immunity; Vaccination
    DOI:  https://doi.org/10.1016/j.livres.2023.05.001
  33. Foods. 2023 Nov 22. pii: 4216. [Epub ahead of print]12(23):
    Modulation of Designed Gut Bacterial Communities by Prebiotics and the Impact of Their Metabolites on Intestinal Cells.
    Dalila Roupar, Abigail González, Joana T Martins, Daniela A Gonçalves, José A Teixeira, Cláudia Botelho, Clarisse Nobre.
      The impact of prebiotics on human health is associated with their capacity to modulate microbiota, improving beneficial microbiota-host interactions. Herein, the prebiotic potential of microbial-fructo-oligosaccharides (microbial-FOSs) produced by a co-culture of Aspergillus ibericus plus Saccharomyces cerevisiae was evaluated on seven- and nine-strain bacterial consortia (7SC and 9SC, respectively), designed to represent the human gut microbiota. The 7SC was composed of Bacteroides dorei, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium longum, Escherichia coli, Lactobacillus acidophilus, and Lactobacillus rhamnosus. The 9SC also comprised the aforementioned bacteria, with the addition of Bacteroides thetaiotaomicron and Roseburia faecis. The effect of microbial-FOSs on the metabolic activity of intestinal Caco-2/HT29-MTX-E12 co-culture was also assessed. The results showed that microbial-FOS selectively promoted the growth of probiotic bacteria and completely suppressed the growth of E. coli. The microbial-FOSs promoted the highest production rates of lactate and total short-chain fatty acids (SCFA) as compared to the commercial prebiotic Frutalose® OFP. Butyrate was only produced in the 9SC consortium, which included the R. faecis-a butyrate-producing bacteria. The inclusion of this bacteria plus another Bacteroides in the 9SC promoted a greater metabolic activity in the Caco-2/HT29-MTX-E12 co-culture. The microbial-FOSs showed potential as promising prebiotics as they selectively promote the growth of probiotic bacteria, producing high concentrations of SCFA, and stimulating the metabolic activity of gut cells.
    Keywords:  Aspergillus ibericus; fructo-oligosaccharides; gut microbiota; in vitro fermentation; intestinal epithelium; prebiotics; short-chain fatty acids
    DOI:  https://doi.org/10.3390/foods12234216
  34. Cell Rep Med. 2024 Jan 16. pii: S2666-3791(23)00577-3. [Epub ahead of print]5(1): 101360
    The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches.
    J R Caldera, Chih-Ming Tsai, Desmond Trieu, Cesia Gonzalez, Irshad A Hajam, Xin Du, Brian Lin, George Y Liu.
      The failure of the Staphylococcus aureus (SA) IsdB vaccine trial can be explained by the recall of non-protective immune imprints from prior SA exposure. Here, we investigate natural human SA humoral imprints to understand their broader impact on SA immunizations. We show that antibody responses against SA cell-wall-associated antigens (CWAs) are non-opsonic, while antibodies against SA toxins are neutralizing. Importantly, the protective characteristics of the antibody imprints accurately predict the failure of corresponding vaccines against CWAs and support vaccination against toxins. In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics.
    Keywords:  S. aureus; antibody interference; immune imprinting; immunization; original antigenic sin; vaccine
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101360
  35. J Tradit Complement Med. 2024 Jan;14(1): 26-39
    Gut-joint axis: Oral Probiotic ameliorates Osteoarthritis.
    Uzma Amin, Rong Jiang, Shahid Masood Raza, Mengtian Fan, Li Liang, Naibo Feng, Xiaoli Li, Yuyou Yang, Fengjin Guo.
      Osteoarthritis (OA) etiology is multifactorial, and its prevalence is growing globally. The Gut microbiota shapes our immune system and impacts all aspects of health and disease. The idea of utilizing probiotics to treat different conditions prevails. Concerning musculoskeletal illness and health, current data lack the link to understand the interactions between the host and microbiome. We report that S. thermophilus, L. pentosus (as probiotics), and γ-aminobutyric acid (GABA) harbour against osteoarthritis in vivo and alleviate IL-1β induced changes in chondrocytes in vitro. We examined the increased GABA concentration in mice's serum and small intestine content followed by bacterial treatment. The treatment inhibited the catabolism of cartilage and rescued mice joints from degradation. Furthermore, the anabolic markers upregulated and decreased inflammatory markers in mice knee joints and chondrocytes. This study is the first to represent GABA's chondrogenic and chondroprotective effects on joints and human chondrocytes. This data provides a foundation for future studies to elucidate the role of GABA in regulating chondrocyte cell proliferation. These findings opened future horizons to understanding the gut-joint axis and OA treatment. Thus, probiotic/GABA therapy shields OA joints in mice and could at least serve as adjuvant therapy to treat osteoarthritis.
    Keywords:  Cartilage degeneration; Chondrogenesis; GABA; Gut microbiota; Inflammation; Joint; Osteoarthritis (OA); Postbiotic; Probiotics
    DOI:  https://doi.org/10.1016/j.jtcme.2023.06.002
  36. Microbiol Immunol. 2024 Jan 17.
    Oral and rectal colonization of methicillin-resistant Staphylococcus aureus in long-term care facility residents and their association with clinical status.
    Satoru Kusaka, Azusa Haruta, Miki Kawada-Matsuo, Mi Nguyen-Tra Le, Mineka Yoshikawa, Toshiki Kajihara, Koji Yahara, Junzo Hisatsune, Ryota Nomura, Kazuhiro Tsuga, Hiroki Ohge, Motoyuki Sugai, Hitoshi Komatsuzawa.
      Staphylococcus aureus is a commensal bacterium in humans, but it sometimes causes opportunistic infectious diseases such as suppurative skin disease, pneumonia, and enteritis. Therefore, it is important to determine the prevalence of S. aureus and methicillin-resistant S. aureus (MRSA) in individuals, especially older adults. In this study, we investigated the prevalence of S. aureus and MRSA in the oral cavity and feces of residents in long-term care facilities (LTCFs). S. aureus was isolated from the oral cavity of 61/178 (34.3%) participants, including 28 MRSA-positive participants (15.7%), and from the feces of 35/127 (27.6%) participants, including 16 MRSA-positive participants (12.6%). S. aureus and MRSA were isolated from both sites in 19/127 individuals (15.0%) and 10/127 individuals (7.9%), respectively. Among 19 participants with S. aureus isolation from both sites, 17 participants showed the same sequence type (ST) type. Then, we analyzed the correlation of S. aureus and MRSA in the oral cavity and rectum with the participant's condition. S. aureus and MRSA positivity in the oral cavity was significantly related to tube feeding, while there was no correlation of rectal S. aureus/MRSA with any factors. Our findings regarding the oral inhabitation of MRSA and its risk factors indicate the importance of considering countermeasures against MRSA infection in LTCFs.
    Keywords:  MRSA; Staphylococcus aureus; antibiotic resistance; long-term care facility; oral cavity
    DOI:  https://doi.org/10.1111/1348-0421.13111
  37. Blood. 2024 Jan 16. pii: blood.2023021380. [Epub ahead of print]
    CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance and immune homeostasis.
    Giorgia Renga, Emilia Nunzi, Claudia Stincardini, Marilena Pariano, Matteo Puccetti, Giuseppe Pieraccini, Claudia Di Serio, Maurizio Fraziano, Noemi Poerio, Vasileios Oikonomou, Paolo Mosci, Enrico Garaci, Luana Fianchi, Livio Pagano, Luigina Romani.
      CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes as it improves survival and outcome of haematopoietic stem cell transplanted patients as compared to the continuous infusion of cytarabine plus daunorubicin (referred to as "7+3" combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily impacts on the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 versus "7+3" combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and "7+3" combination on mucosal barrier function, gut microbial composition and function and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with "7+3" combination, protected from gut dysbiosis, mucosal damage and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-IL-22-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.
    DOI:  https://doi.org/10.1182/blood.2023021380
  38. Am J Respir Crit Care Med. 2024 Jan 16.
    Looking Beyond the Lower Airways for Microbes Affecting Pulmonary Fibrosis.
    Fares Darawshy, Philip L Molyneaux, Leopoldo N Segal.
      
    DOI:  https://doi.org/10.1164/rccm.202312-2255ED
  39. Microbiol Res. 2024 Jan 03. pii: S0944-5013(23)00298-7. [Epub ahead of print]281 127595
    Atopic dermatitis: Pathophysiology, microbiota, and metabolome - A comprehensive review.
    Shahnawaz Mohammad, Md Rezaul Karim, Safia Iqbal, Jung Hyeok Lee, Ramya Mathiyalagan, Yeon Ju Kim, Dong Uk Yang, Deok Chun Yang.
      Atopic dermatitis (AD) is a prevalent inflammatory skin condition that commonly occurs in children. Genetics, environment, and defects in the skin barrier are only a few of the factors that influence how the disease develops. As human microbiota research has advanced, more scientific evidence has shown the critical involvement of the gut and skin bacteria in the pathogenesis of atopic dermatitis. Microbiome dysbiosis, defined by changed diversity and composition, as well as the development of pathobionts, has been identified as a potential cause for recurring episodes of atopic dermatitis. Gut dysbiosis causes "leaky gut syndrome" by disrupting the epithelial lining of the gut, which allows bacteria and other endotoxins to enter the bloodstream and cause inflammation. The same is true for the disruption of cutaneous homeostasis caused by skin dysbiosis, which enables bacteria and other pathogens to reach deeper skin layers or even systemic circulation, resulting in inflammation. Furthermore, it is now recognized that the gut and skin microbiota releases both beneficial and toxic metabolites. Here, this review covers a range of topics related to AD, including its pathophysiology, the microbiota-AD connection, commonly used treatments, and the significance of metabolomics in AD prevention, treatment, and management, recognizing its potential in providing valuable insights into the disease.
    Keywords:  Atopic dermatitis; Gut-skin microbial dysbiosis; Homeostasis; Metabolomics; Pathophysiology
    DOI:  https://doi.org/10.1016/j.micres.2023.127595
  40. Cell Commun Signal. 2024 Jan 15. 22(1): 40
    Pyroptosis: a double-edged sword in lung cancer and other respiratory diseases.
    Xiao Liang, Ya Qin, Dan Wu, Qiong Wang, Hongshuai Wu.
      Pyroptosis is an active cell death process mediated by gasdermin family proteins including Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME, DFNA5), and DFNB59. Emerging evidences have shown that pyroptosis contributes to many pulmonary diseases, especially lung cancer, and pneumonia. The exact roles of pyroptosis and gasdermin family proteins are tremendously intricate. Besides, there are evidences that pyroptosis contributes to these respiratory diseases. However, it often plays a dual role in these diseases which is a cause for concern and makes it difficult for clinical translation. This review will focus on the multifaceted roles of pyroptosis in respiratory diseases.
    Keywords:  Caspase; Gasdermin; Lung cancer; Pneumonia; Pyroptosis
    DOI:  https://doi.org/10.1186/s12964-023-01458-w
  41. J Innate Immun. 2024 Jan 15.
    The Role of Neutrophil in COVID-19 - Positive or Negative.
    Na Rong, Xiaohui Wei, Jiangning Liu.
      Background Neutrophils are the first line of defense against pathogens. They are divided into multiple subpopulations during development and kill pathogens through various mechanisms. Neutrophils are considered one of the markers of severe COVID-19. Summary In-depth research has revealed that neutrophil subpopulations have multiple complex functions. Different subsets of neutrophils play an important role in the progression of COVID-19. Key Messages In this review, we provide a detailed overview of the developmental processes of neutrophils at different stages and their recruitment and activation after SARS-CoV-2 infection, aiming to elucidate the changes in neutrophil subpopulations, characteristics, and functions after infection and provide a reference for mechanistic research on neutrophil subpopulations in the context of SARS-CoV-2 infection. In addition, we have also summarized research progress on potential targeted drugs for neutrophil immunotherapy, hoping to provide information that aids the development of therapeutic drugs for the clinical treatment of critically ill COVID-19 patients.
    DOI:  https://doi.org/10.1159/000535541
  42. Methods Mol Biol. 2024 ;2741 73-100
    Ribosome Profiling Methods Adapted to the Study of RNA-Dependent Translation Regulation in Staphylococcus aureus.
    Maximilian P Kohl, Béatrice Chane-Woon-Ming, Roberto Bahena-Ceron, Jose Jaramillo-Ponce, Laura Antoine, Lucas Herrgott, Pascale Romby, Stefano Marzi.
      Noncoding RNAs, including regulatory RNAs (sRNAs), are instrumental in regulating gene expression in pathogenic bacteria, allowing them to adapt to various stresses encountered in their host environments. Staphylococcus aureus is a well-studied model for RNA-mediated regulation of virulence and pathogenicity, with sRNAs playing significant roles in shaping S. aureus interactions with human and animal hosts. By modulating the translation and/or stability of target mRNAs, sRNAs regulate the synthesis of virulence factors and regulatory proteins required for pathogenesis. Moreover, perturbation of the levels of RNA modifications in two other classes of noncoding RNAs, rRNAs, and tRNAs, has been proposed to contribute to stress adaptation. However, the study of how these various factors affect translation regulation has often been restricted to specific genes, using in vivo reporters and/or in vitro translation systems. Genome-wide sequencing approaches offer novel perspectives for studying RNA-dependent regulation. In particular, ribosome profiling methods provide a powerful resource for characterizing the overall landscape of translational regulation, contributing to a better understanding of S. aureus physiopathology. Here, we describe protocols that we have adapted to perform ribosome profiling in S. aureus.
    Keywords:  Ribo-RET; Ribo-seq; Ribosome profiling; Staphylococcus aureus; Start codons; Translation initiation; Translation regulation
    DOI:  https://doi.org/10.1007/978-1-0716-3565-0_5
  43. Nat Rev Cancer. 2024 Jan 15.
    Epigenetic memory.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-024-00667-w
  44. Curr Top Microbiol Immunol. 2023 ;444 207-238
    Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori.
    Michael Naumann, Lorena Ferino, Irshad Sharafutdinov, Steffen Backert.
      Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H. pylori infection represents a prime example of chronic inflammation and cancer-inducing bacterial pathogens. The microbe utilizes a remarkable set of virulence factors and strategies to control cellular checkpoints of inflammation and oncogenic signal transduction. This chapter emphasizes on the pathogenicity determinants of H. pylori such as the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system (T4SS), effector protein CagA, lipopolysaccharide (LPS) metabolite ADP-glycero-β-D-manno-heptose (ADP-heptose), cytotoxin VacA, serine protease HtrA, and urease, and how they manipulate various key host cell signaling networks in the gastric epithelium. In particular, we highlight the H. pylori-induced disruption of cell-to-cell junctions, pro-inflammatory activities, as well as proliferative, pro-apoptotic and anti-apoptotic responses. Here we review these hijacked signal transduction events and their impact on gastric disease development.
    Keywords:  ALPK1; Cortactin; NF-κB; TIFA; Wnt
    DOI:  https://doi.org/10.1007/978-3-031-47331-9_8
  45. Front Immunol. 2023 ;14 1281096
    Microbial evasion of the complement system: a continuous and evolving story.
    Mariam T Heggi, Hanzada T Nour El-Din, Dina I Morsy, Noha I Abdelaziz, Ahmed S Attia.
      The complement system is a fundamental part of the innate immune system that plays a key role in the battle of the human body against invading pathogens. Through its three pathways, represented by the classical, alternative, and lectin pathways, the complement system forms a tightly regulated network of soluble proteins, membrane-expressed receptors, and regulators with versatile protective and killing mechanisms. However, ingenious pathogens have developed strategies over the years to protect themselves from this complex part of the immune system. This review briefly discusses the sequence of the complement activation pathways. Then, we present a comprehensive updated overview of how the major four pathogenic groups, namely, bacteria, viruses, fungi, and parasites, control, modulate, and block the complement attacks at different steps of the complement cascade. We shed more light on the ability of those pathogens to deploy more than one mechanism to tackle the complement system in their path to establish infection within the human host.
    Keywords:  complement evasion; pathogens; regulation; serum resistance; virulence factors
    DOI:  https://doi.org/10.3389/fimmu.2023.1281096
  46. J Transl Autoimmun. 2024 Jun;8 100228
    ANKRD22 aggravates sepsis-induced ARDS and promotes pulmonary M1 macrophage polarization.
    Shi Zhang, Yao Liu, Xiao-Long Zhang, Yun Sun, Zhong-Hua Lu.
      Acute respiratory distress syndrome (ARDS) is independently associated with a poor prognosis in patients with sepsis. Macrophage M1 polarization plays an instrumental role in this process. Therefore, the exploration of key molecules affecting acute lung injury and macrophage M1 polarization may provide therapeutic targets for the treatment of septic ARDS. Here, we identified that elevated levels of Ankyrin repeat domain-containing protein 22 (ANKRD22) were associated with poor prognosis and more pronounced M1 macrophage polarization in septic patients by analyzing high-throughput data. ANKRD22 expression was also significantly upregulated in the alveolar lavage fluid, peripheral blood, and lung tissue of septic ARDS model mice. Knockdown of ANKRD22 significantly attenuated acute lung injury in mice with sepsis-induced ARDS and reduced the M1 polarization of lung macrophages. Furthermore, deletion of ANKRD22 in macrophages inhibited M1 macrophage polarization and reduced levels of phosphorylated IRF3 and intracellular interferon regulatory factor 3 (IRF3) expression, while re-expression of ANKRD22 reversed these changes. Further experiments revealed that ANKRD22 promotes IRF3 activation by binding to mitochondrial antiviral-signaling protein (MAVS). In conclusion, these findings suggest that ANKRD22 promotes the M1 polarization of lung macrophages and exacerbates sepsis-induced ARDS.
    Keywords:  ANKRD22; Acute lung injury; Acute respiratory distress syndrome (ARDS); Inflammatory response; Macrophage; Sepsis
    DOI:  https://doi.org/10.1016/j.jtauto.2023.100228
  47. mBio. 2024 Jan 18. e0027723
    Yersiniabactin is a quorum-sensing autoinducer and siderophore in uropathogenic Escherichia coli.
    James R Heffernan, John A Wildenthal, Hung Tran, George L Katumba, William H McCoy, Jeffrey P Henderson.
      IMPORTANCE: Patients with urinary tract infections are often infected with Escherichia coli strains carrying adaptations that increase their pathogenic potential. One of these adaptations is the accumulation of multiple siderophore systems, which scavenge iron for nutritional use. While iron uptake is important for bacterial growth, the increased metabolic costs of siderophore production could diminish bacterial fitness during infections. In a siderophore-dependent growth condition, we show that the virulence-associated yersiniabactin siderophore system in uropathogenic E. coli is not redundant with the ubiquitous E. coli enterobactin system. This arises not from differences in iron-scavenging activity but because yersiniabactin is preferentially expressed during bacterial crowding, leaving bacteria dependent upon enterobactin for growth at low cell density. Notably, this regulatory mode arises because yersiniabactin stimulates its own expression, acting as an autoinducer in a previously unappreciated quorum-sensing system. This unexpected result connects quorum-sensing with pathogenic potential in E. coli and related Enterobacterales.
    Keywords:  Escherichia coli; host-pathogen interactions; iron acquisition; metabolic regulation; quorum sensing; secondary metabolism; siderophores; urinary tract infection; virulence regulation
    DOI:  https://doi.org/10.1128/mbio.00277-23
  48. bioRxiv. 2023 Dec 30. pii: 2023.12.30.573720. [Epub ahead of print]
    Vaginal Lactobacillus fatty acid response mechanisms reveal a novel strategy for bacterial vaginosis treatment.
    Meilin Zhu, Matthew W Frank, Christopher D Radka, Sarah Jeanfavre, Megan W Tse, Julian Avila Pacheco, Kerry Pierce, Amy Deik, Jiawu Xu, Salina Hussain, Fatima Aysha Hussain, Nondumiso Xulu, Nasreen Khan, Vanessa Pillay, Krista L Dong, Thumbi Ndung'u, Clary B Clish, Charles O Rock, Paul C Blainey, Seth M Bloom, Douglas S Kwon.
      Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus -deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus , which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related species, including an oleate hydratase ( ohyA ) and putative fatty acid efflux pump ( farE ). FarE mediates OA resistance, while OhyA is robustly active in the human vaginal microbiota and sequesters OA in a derivative form that only ohyA -harboring organisms can exploit. Finally, OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro model of BV, suggesting a novel approach for treatment.
    DOI:  https://doi.org/10.1101/2023.12.30.573720
  49. Cell Mol Immunol. 2024 Jan 17.
    Tissue-resident macrophages exacerbate lung injury after remote sterile damage.
    Hanhui Zhong, Jingjing Ji, Jinling Zhuang, Ziying Xiong, Pengyun Xie, Xiaolei Liu, Jundi Zheng, Wangli Tian, Xiaoyang Hong, Jing Tang.
      Remote organ injury, which is a common secondary complication of sterile tissue damage, is a major cause of poor prognosis and is difficult to manage. Here, we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response. We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke. Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products (RAGE) on the membrane, which activated epidermal growth factor receptor (EGFR). Mechanistically, ligand-activated RAGE triggered EGFR activation through an interaction, leading to Rab5-mediated RAGE internalization and EGFR phosphorylation, which subsequently recruited and activated P38; this, in turn, promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands, consequently exacerbating inflammation. Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages, blocking the function of RAGE with a neutralizing antibody, or pharmacological inhibition of EGFR activation in macrophages could protect against trauma- or stroke-induced remote lung injury. Therefore, our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.
    Keywords:  RAGE; remote sterile damage; tissue-resident macrophage
    DOI:  https://doi.org/10.1038/s41423-024-01125-1
  50. Curr Opin Microbiol. 2024 Jan 13. pii: S1369-5274(23)00157-1. [Epub ahead of print]77 102420
    Group A Streptococcus interactions with the host across time and space.
    Stephanie Guerra, Christopher LaRock.
      Group A Streptococcus (GAS) has a fantastically wide tissue tropism in humans, manifesting as different diseases depending on the strain's virulence factor repertoire and the tissue involved. Activation of immune cells and pro-inflammatory signaling has historically been considered an exclusively host-protective response that a pathogen would seek to avoid. However, recent advances in human and animal models suggest that in some tissues, GAS will activate and manipulate specific pro-inflammatory pathways to promote growth, nutrient acquisition, persistence, recurrent infection, competition with other microbial species, dissemination, and transmission. This review discusses molecular interactions between the host and pathogen to summarize how infection varies across tissue and stages of inflammation. A need for inflammation for GAS survival during common, mild infections may drive selection for mechanisms that cause pathological and excess inflammation severe diseases such as toxic shock syndrome, necrotizing fasciitis, and rheumatic heart disease.
    DOI:  https://doi.org/10.1016/j.mib.2023.102420
  51. Nat Commun. 2024 Jan 15. 15(1): 541
    Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis.
    Linnea Z Drexhage, Shengpan Zhang, Maeva Dupont, Franziska Ragaller, Ellen Sjule, Jose Cabezas-Caballero, Lachlan P Deimel, Helen Robertson, Rebecca A Russell, Omer Dushek, Erdinc Sezgin, Niloofar Karaji, Quentin J Sattentau.
      Efferocytic clearance of apoptotic cells in general, and T cells in particular, is required for tissue and immune homeostasis. Transmembrane mucins are extended glycoproteins highly expressed in the cell glycocalyx that function as a barrier to phagocytosis. Whether and how mucins may be regulated during cell death to facilitate efferocytic corpse clearance is not well understood. Here we show that normal and transformed human T cells express a subset of mucins which are rapidly and selectively removed from the cell surface during apoptosis. This process is mediated by the ADAM10 sheddase, the activity of which is associated with XKR8-catalyzed flipping of phosphatidylserine to the outer leaflet of the plasma membrane. Mucin clearance enhances uptake of apoptotic T cells by macrophages, confirming mucins as an enzymatically-modulatable barrier to efferocytosis. Together these findings demonstrate a glycocalyx regulatory pathway with implications for therapeutic intervention in the clearance of normal and transformed apoptotic T cells.
    DOI:  https://doi.org/10.1038/s41467-023-44619-8
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