bims-bac4me 2023-01-15 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023‒01‒15
fifteen papers selected by
Chun-Chi Chang
University Hospital Zurich

Understanding respiratory microbiome-immune system interactions in health and disease.
The intestinal microenvironment shapes macrophage and dendritic cell identity and function.
Immune evasion and persistence in enteric bacterial pathogens.
Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health.
IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses.
Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development.
Biofilm Formation by Staphylococcus aureus in the Specific Context of Cystic Fibrosis.
GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology.
Metabolites as signalling molecules.
The complement system as a key modulator of the oral microbiome in health and disease.
Canonical and non-canonical functions of NLRP3.
Inside the phagosome: A bacterial perspective.
The resistance mechanisms of bacteria against ciprofloxacin and new approaches for enhancing the efficacy of this antibiotic.
Within-host evolution of the gut microbiome.
Extracellular vesicle-mediated regulation of macrophage polarization in bacterial infections.

Sci Transl Med. 2023 Jan 11. 15(678): eabq5126

Understanding respiratory microbiome-immune system interactions in health and disease.

Sara K Di Simone, Ina Rudloff, Claudia A Nold-Petry, Samuel C Forster, Marcel F Nold.

Interactions between the developing microbiome and maturing immune system in early life are critical for establishment of a homeostasis beneficial to both host and commensals. The lung harbors a diverse community of microbes associated with health and local or systemic disease. We discuss how early life colonization and community changes correlate with immune development and health and disease throughout infancy, childhood, and adult life. We highlight key advances in microbiology, immunology, and computational biology that allow investigation of the functional relevance of interactions between the respiratory microbiome and host immune system, which may unlock the potential for microbiome-based therapeutics.

DOI: https://doi.org/10.1126/scitranslmed.abq5126
Immunol Lett. 2023 Jan 07. pii: S0165-2478(23)00003-2. [Epub ahead of print]253 41-53

The intestinal microenvironment shapes macrophage and dendritic cell identity and function.

Alessandra A Filardy, Jesuino R M Ferreira, Rafael M Rezende, Brian L Kelsall, Rafael P Oliveira.

  The gut comprises the largest body interface with the environment and is continuously exposed to nutrients, food antigens, and commensal microbes, as well as to harmful pathogens. Subsets of both macrophages and dendritic cells (DCs) are present throughout the intestinal tract, where they primarily inhabit the gut-associate lymphoid tissue (GALT), such as Peyer's patches and isolated lymphoid follicles. In addition to their role in taking up and presenting antigens, macrophages and DCs possess extensive functional plasticity and these cells play complementary roles in maintaining immune homeostasis in the gut by preventing aberrant immune responses to harmless antigens and microbes and by promoting host defense against pathogens. The ability of macrophages and DCs to induce either inflammation or tolerance is partially lineage imprinted, but can also be dictated by their activation state, which in turn is determined by their specific microenvironment. These cells express several surface and intracellular receptors that detect danger signals, nutrients, and hormones, which can affect their activation state. DCs and macrophages play a fundamental role in regulating T cells and their effector functions. Thus, modulation of intestinal mucosa immunity by targeting antigen presenting cells can provide a promising approach for controlling pathological inflammation. In this review, we provide an overview on the characteristics, functions, and origins of intestinal macrophages and DCs, highlighting the intestinal microenvironmental factors that influence their functions during homeostasis. Unraveling the mechanisms by which macrophages and DCs regulate intestinal immunity will deepen our understanding on how the immune system integrates endogenous and exogenous signals in order to maintain the host's homeostasis.

Keywords:  Colon; Diet-derived antigens; Environmental immunomodulators; Microbiota; Small intestine

DOI:  https://doi.org/10.1016/j.imlet.2023.01.003
Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2163839

Immune evasion and persistence in enteric bacterial pathogens.

Micah J Worley.

  The major function of the mammalian immune system is to prevent and control infections caused by enteropathogens that collectively have altered human destiny. In fact, as the gastrointestinal tissues are the major interface of mammals with the environment, up to 70% of the human immune system is dedicated to patrolling them The defenses are multi-tiered and include the endogenous microflora that mediate colonization resistance as well as physical barriers intended to compartmentalize infections. The gastrointestinal tract and associated lymphoid tissue are also protected by sophisticated interleaved arrays of active innate and adaptive immune defenses. Remarkably, some bacterial enteropathogens have acquired an arsenal of virulence factors with which they neutralize all these formidable barriers to infection, causing disease ranging from mild self-limiting gastroenteritis to in some cases devastating human disease.

Keywords:  Campylobacter; Immune evasion; Salmonella; Shigella; Vibrio; Yersinia; colonization resistance; inflammation; persistence

DOI:  https://doi.org/10.1080/19490976.2022.2163839
Cells. 2023 Jan 02. pii: 184. [Epub ahead of print]12(1):

Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health.

Chiara Mazziotta, Mauro Tognon, Fernanda Martini, Elena Torreggiani, John Charles Rotondo.

  Immune cells and commensal microbes in the human intestine constantly communicate with and react to each other in a stable environment in order to maintain healthy immune activities. Immune system-microbiota cross-talk relies on a complex network of pathways that sustain the balance between immune tolerance and immunogenicity. Probiotic bacteria can interact and stimulate intestinal immune cells and commensal microflora to modulate specific immune functions and immune homeostasis. Growing evidence shows that probiotic bacteria present important health-promoting and immunomodulatory properties. Thus, the use of probiotics might represent a promising approach for improving immune system activities. So far, few studies have been reported on the beneficial immune modulatory effect of probiotics. However, many others, which are mainly focused on their metabolic/nutritional properties, have been published. Therefore, the mechanisms behind the interaction between host immune cells and probiotics have only been partially described. The present review aims to collect and summarize the most recent scientific results and the resulting implications of how probiotic bacteria and immune cells interact to improve immune functions. Hence, a description of the currently known immunomodulatory mechanisms of probiotic bacteria in improving the host immune system is provided.

Keywords:  beneficial microbes; human health; immune cells; immune modulation; immune response; immune system; microbial modulation effects; microbiome; microbiota; probiotics

DOI:  https://doi.org/10.3390/cells12010184
Front Immunol. 2022 ;13 1028789

IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses.

Sarah Frentzel, Andreas Jeron, Alexander Pausder, Olivia Kershaw, Julia Volckmar, Ingo Schmitz, Dunja Bruder.

  IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6Chigh inflammatory monocytes prompted us to further characterize the specific contribution of IκBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chigh monocytes primed during Lm infection in the absence of IκBNS displayed a blunted response compared to wild type-derived Ly6Chigh monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNS during Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chigh monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNS as molecular driver of inflammation in listeriosis.

Keywords:  IκBNS; Listeria monocytogenes; hyper-inflammation; in vivo infection; innate immunity; myeloid cells

DOI:  https://doi.org/10.3389/fimmu.2022.1028789
Front Cell Infect Microbiol. 2022 ;12 1060810

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development.

Tania Wong Fok Lung, Liana C Chan, Alice Prince, Michael R Yeaman, Nathan K Archer, M Javad Aman, Richard A Proctor.

  Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

Keywords:  S. aureus; human epigenetics; human genetics; immunity; immunometabolites; vaccine

DOI:  https://doi.org/10.3389/fcimb.2022.1060810
Int J Mol Sci. 2022 Dec 29. pii: 597. [Epub ahead of print]24(1):

Biofilm Formation by Staphylococcus aureus in the Specific Context of Cystic Fibrosis.

Vincent Jean-Pierre, Agathe Boudet, Pauline Sorlin, Quentin Menetrey, Raphaël Chiron, Jean-Philippe Lavigne, Hélène Marchandin.

  Staphylococcus aureus is a major human pathogen whose characteristics support its success in various clinical settings including Cystic Fibrosis (CF). In CF, S. aureus is indeed the most commonly identified opportunistic pathogen in children and the overall population. S. aureus colonization/infection, either by methicillin-susceptible or methicillin-resistant strains, will become chronic in about one third of CF patients. The persistence of S. aureus in CF patients' lungs, despite various eradication strategies, is favored by several traits in both host and pathogen. Among the latter, living in biofilm is a highly protective way to survive despite deleterious environmental conditions, and is a common characteristic shared by the main pathogens identified in CF. This is why CF has earned the status of a biofilm-associated disease for several years now. Biofilm formation by S. aureus, and the molecular mechanisms governing and regulating it, have been extensively studied but have received less attention in the specific context of CF lungs. Here, we review the current knowledge on S. aureus biofilm in this very context, i.e., the importance, study methods, molecular data published on mono- and multi-species biofilm and anti-biofilm strategies. This focus on studies including clinical isolates from CF patients shows that they are still under-represented in the literature compared with studies based on reference strains, and underlines the need for such studies. Indeed, CF clinical strains display specific characteristics that may not be extrapolated from results obtained on laboratory strains.

Keywords:  Staphylococcus aureus; anti-biofilm; biofilm; cystic fibrosis; multispecies biofilm

DOI:  https://doi.org/10.3390/ijms24010597
Immunity. 2023 Jan 10. pii: S1074-7613(22)00645-8. [Epub ahead of print]56(1): 43-57.e10

GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology.

Zachary M Earley, Wioletta Lisicka, Joseph J Sifakis, Raúl Aguirre-Gamboa, Anita Kowalczyk, Jacob T Barlow, Dustin G Shaw, Valentina Discepolo, Ineke L Tan, Saideep Gona, Jordan D Ernest, Polly Matzinger, Luis B Barreiro, Andrey Morgun, Albert Bendelac, Rustem F Ismagilov, Natalia Shulzhenko, Samantha J Riesenfeld, Bana Jabri.

  There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.

Keywords:  GATA4; IgA; bacterial colonization; celiac disease; immunopathology; infection; intestinal epithelial cells; intestinal regionalization; retinoic acid; segmented filamentous bacteria

DOI:  https://doi.org/10.1016/j.immuni.2022.12.009
Nat Rev Mol Cell Biol. 2023 Jan 12.

Metabolites as signalling molecules.

Steven Andrew Baker, Jared Rutter.

Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.

DOI: https://doi.org/10.1038/s41580-022-00572-w
Crit Rev Microbiol. 2023 Jan 09. 1-30

The complement system as a key modulator of the oral microbiome in health and disease.

Renata O Mattos-Graner, Marlise I Klein, Lívia Araújo Alves.

  In this review, we address the interplay between the complement system and host microbiomes in health and disease, focussing on oral bacteria known to contribute to homeostasis or to promote dysbiosis associated with dental caries and periodontal diseases. Host proteins modulating complement activities in the oral environment and expression profiles of complement proteins in oral tissues were described. In addition, we highlight a sub-set of bacterial proteins involved in complement evasion and/or dysregulation previously characterized in pathogenic species (or strains), but further conserved among prototypical commensal species of the oral microbiome. Potential roles of these proteins in host-microbiome homeostasis and in the emergence of commensal strain lineages with increased virulence were also addressed. Finally, we provide examples of how commensal bacteria might exploit the complement system in competitive or cooperative interactions within the complex microbial communities of oral biofilms. These issues highlight the need for studies investigating the effects of the complement system on bacterial behaviour and competitiveness during their complex interactions within oral and extra-oral host sites.

Keywords:  Oral microbiome; complement system; dental biofilms; dental caries; streptococci

DOI:  https://doi.org/10.1080/1040841X.2022.2163614
J Adv Res. 2023 Jan 04. pii: S2090-1232(23)00001-2. [Epub ahead of print]

Canonical and non-canonical functions of NLRP3.

Théo Accogli, Christophe Hibos, Frédérique Vegran.

  BACKGROUND: Since its discovery, NLRP3 is almost never separated from its major role in the protein complex it forms with ASC, NEK7 and Caspase-1, the inflammasome. This key component of the innate immune response mediates the secretion of proinflammatory cytokines IL-1β and IL-18 involved in immune response to microbial infection and cellular damage. However, NLRP3 has also other functions that do not involve the inflammasome assembly nor the innate immune response. These non-canonical functions have been poorly studied. Nevertheless, NLRP3 is associated with different kind of diseases probably through its inflammasome dependent function as through its inflammasome independent functions.AIM OF THE REVIEW: The study and understanding of the canonical and non-canonical functions of NLRP3 can help to better understand its involvement in various pathologies. In parallel, the description of the mechanisms of action and regulation of its various functions, can allow the identification of new therapeutic strategies.
KEY SCIENTIFIC CONCEPTS OF THE REVIEW: NLRP3 functions have mainly been studied in the context of the inflammasome, in myeloid cells and in totally deficient transgenic mice. However, for several year, the work of different teams has proven that NLRP3 is also expressed in other cell types where it has functions that are independent of the inflammasome. If these studies suggest that NLRP3 could play different roles in the cytoplasm or the nucleus of the cells, the mechanisms underlying NLRP3 non-canonical functions remain unclear. This is why we propose in this review an inventory of the canonical and non-canonical functions of NLRP3 and their impact in different pathologies.

Keywords:  Inflammasome; Myeloid cells; NLRP3; Uncanonical functions

DOI:  https://doi.org/10.1016/j.jare.2023.01.001
Immunol Rev. 2023 Jan 10.

Inside the phagosome: A bacterial perspective.

Mark B Hampton, Nina Dickerhof.

  The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense mechanisms should lead to new therapies that assist neutrophils to kill pathogens, but this has not yet come to fruition. One of the limiting factors in this effort has been our incomplete knowledge of the complex biochemistry that occurs within the rapidly changing environment of the phagosome. The same compartmentalization that protects host tissue also limits our ability to measure events within the phagosome. In this review, we highlight the limitations in our knowledge, and how the contribution of bacteria to the phagosomal environment is often ignored. There appears to be significant heterogeneity among phagosomes, and it is important to determine whether survivors have more efficient defenses or whether they are ingested into less threatening environments than other bacteria. As part of these efforts, we discuss how monitoring or recovering bacteria from phagosomes can provide insight into the conditions they have faced. We also encourage the use of unbiased screening approaches to identify bacterial genes that are essential for survival inside neutrophil phagosomes.

Keywords:  bacterial killing; myeloperoxidase; neutrophils; oxidative stress; phagosome; thiols

DOI:  https://doi.org/10.1111/imr.13182
Front Public Health. 2022 ;10 1025633

The resistance mechanisms of bacteria against ciprofloxacin and new approaches for enhancing the efficacy of this antibiotic.

Aref Shariati, Maniya Arshadi, Mohammad Ali Khosrojerdi, Mostafa Abedinzadeh, Mahsa Ganjalishahi, Abbas Maleki, Mohsen Heidary, Saeed Khoshnood.

  For around three decades, the fluoroquinolone (FQ) antibiotic ciprofloxacin has been used to treat a range of diseases, including chronic otorrhea, endocarditis, lower respiratory tract, gastrointestinal, skin and soft tissue, and urinary tract infections. Ciprofloxacin's main mode of action is to stop DNA replication by blocking the A subunit of DNA gyrase and having an extra impact on the substances in cell walls. Available in intravenous and oral formulations, ciprofloxacin reaches therapeutic concentrations in the majority of tissues and bodily fluids with a low possibility for side effects. Despite the outstanding qualities of this antibiotic, Salmonella typhi, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa have all shown an increase in ciprofloxacin resistance over time. The rise of infections that are resistant to ciprofloxacin shows that new pharmacological synergisms and derivatives are required. To this end, ciprofloxacin may be more effective against the biofilm community of microorganisms and multi-drug resistant isolates when combined with a variety of antibacterial agents, such as antibiotics from various classes, nanoparticles, natural products, bacteriophages, and photodynamic therapy. This review focuses on the resistance mechanisms of bacteria against ciprofloxacin and new approaches for enhancing its efficacy.

Keywords:  antibacterial agents; ciprofloxacin; new approach; resistance; review

DOI:  https://doi.org/10.3389/fpubh.2022.1025633
Curr Opin Microbiol. 2023 Jan 04. pii: S1369-5274(22)00142-4. [Epub ahead of print]71 102258

Within-host evolution of the gut microbiome.

Tanja Dapa, Daniel Pgh Wong, Kimberly S Vasquez, Karina B Xavier, Kerwyn Casey Huang, Benjamin H Good.

Gut bacteria inhabit a complex environment that is shaped by interactions with their host and the other members of the community. While these ecological interactions have evolved over millions of years, mounting evidence suggests that gut commensals can evolve on much shorter timescales as well, by acquiring new mutations within individual hosts. In this review, we highlight recent progress in understanding the causes and consequences of short-term evolution in the mammalian gut, from experimental evolution in murine hosts to longitudinal tracking of human cohorts. We also discuss new opportunities for future progress by expanding the repertoire of focal species, hosts, and surrounding communities, and by combining deep-sequencing technologies with quantitative frameworks from population genetics.

DOI: https://doi.org/10.1016/j.mib.2022.102258
Front Microbiol. 2022 ;13 1039040

Extracellular vesicle-mediated regulation of macrophage polarization in bacterial infections.

Mingjuan Qu, Hongwei Zhu, Xingxiao Zhang.

  Extracellular vesicles (EVs) are nanoscale membrane-enveloped vesicles secreted by prokaryotic and eukaryotic cells, which are commonly defined as membrane vesicles (MVs) and exosomes, respectively. They play critical roles in the bacteria-bacteria and bacteria-host interactions. In infectious diseases caused by bacteria, as the first line of defense against pathogens, the macrophage polarization mode commonly determines the success or failure of the host's response to pathogen aggression. M1-type macrophages secrete pro-inflammatory factors that support microbicidal activity, while alternative M2-type macrophages secrete anti-inflammatory factors that perform an antimicrobial immune response but partially allow pathogens to replicate and survive intracellularly. Membrane vesicles (MVs) released from bacteria as a distinctive secretion system can carry various components, including bacterial effectors, nucleic acids, or lipids to modulate macrophage polarization in host-pathogen interaction. Similar to MVs, bacteria-infected macrophages can secrete exosomes containing a variety of components to manipulate the phenotypic polarization of "bystander" macrophages nearby or long distance to differentiate into type M1 or M2 to regulate the course of inflammation. Exosomes can also repair tissue damage associated with the infection by upregulating the levels of anti-inflammatory factors, downregulating the pro-inflammatory factors, and regulating cellular biological behaviors. The study of the mechanisms by which EVs modulate macrophage polarization has opened new frontiers in delineating the molecular machinery involved in bacterial pathogenesis and challenges in providing new strategies for diagnosis and therapy.

Keywords:  bacterial infectious diseases; exosome; extracellular vesicles; macrophage polarization; membrane vesicles

DOI:  https://doi.org/10.3389/fmicb.2022.1039040