bims-bac4me 2023-02-05 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023‒02‒05
nine papers selected by
Chun-Chi Chang
University Hospital Zurich

Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.
A Staphylococcal Glucosaminidase Drives Inflammatory Responses by Processing Peptidoglycan Chains to Physiological Lengths.
Bacterial Crosstalk via Antimicrobial Peptides on the Human Skin: Therapeutics from a Sustainable Perspective.
Immunological consequences of microbiome-based therapeutics.
Rhinovirus increases Moraxella catarrhalis adhesion to the respiratory epithelium.
IL-17 signaling in keratinocytes orchestrates the defense against Staphylococcus aureus skin infection.
Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling.
Oral Vaccination with Engineered Probiotic Limosilactobacillus reuteri Has Protective Effects against Localized and Systemic Staphylococcus aureus Infection.
Skin colonization with S. aureus can lead to increased NLRP1 inflammasome activation in patients with atopic dermatitis.

Cell Rep. 2023 Jan 31. pii: S2211-1247(23)00075-X. [Epub ahead of print]42(2): 112064

Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.

Kira L Tomlinson, Sebastián A Riquelme, Swikrity Upadhyay Baskota, Marija Drikic, Ian R Monk, Timothy P Stinear, Ian A Lewis, Alice S Prince.

  Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can evade immune clearance. Here, we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects the lung from excessive inflammation but compromises bacterial clearance. S. aureus is thus able to evade the innate immune response by targeting neutrophil metabolism and inducing the production of the anti-inflammatory metabolite itaconate.

Keywords:  CP: Immunology; CP: Microbiology; NADPH oxidase; Staphylococcus aureus; itaconate; neutrophils; oxidative burst; pathogenesis; pneumonia

DOI:  https://doi.org/10.1016/j.celrep.2023.112064
Infect Immun. 2023 Jan 30. e0050022

A Staphylococcal Glucosaminidase Drives Inflammatory Responses by Processing Peptidoglycan Chains to Physiological Lengths.

Zachary J Resko, Caleb M Anderson, Michael J Federle, Francis Alonzo.

  The peptidoglycan of Staphylococcus aureus is a critical cell envelope constituent and virulence factor that subverts host immune defenses and provides protection against environmental stressors. Peptidoglycan chains of the S. aureus cell wall are processed to characteristically short lengths by the glucosaminidase SagB. It is well established that peptidoglycan is an important pathogen-associated molecular pattern (PAMP) that is recognized by the host innate immune system and promotes production of proinflammatory cytokines, including interleukin-1β (IL-1β). However, how bacterial processing of peptidoglycan drives IL-1β production is comparatively unexplored. Here, we tested the involvement of staphylococcal glucosaminidases in shaping innate immune responses and identified SagB as a mediator of IL-1β production. A ΔsagB mutant fails to promote IL-1β production by macrophages and dendritic cells, and processing of peptidoglycan by SagB is essential for this response. SagB-dependent IL-1β production by macrophages is independent of canonical pattern recognition receptor engagement and NLRP3 inflammasome-mediated caspase activity. Instead, treatment of macrophages with heat-killed cells from a ΔsagB mutant leads to reduced caspase-independent cleavage of pro-IL-1β, resulting in accumulation of the pro form in the macrophage cytosol. Furthermore, SagB is required for virulence in systemic infection and promotes IL-1β production in a skin and soft tissue infection model. Taken together, our results suggest that the length of S. aureus cell wall glycan chains can drive IL-1β production by innate immune cells through a previously undescribed mechanism related to IL-1β maturation.

Keywords:  IL-1β; SagB; Staphylococcus aureus; glucosaminidase; inflammation; innate immunity; macrophage; peptidoglycan

DOI:  https://doi.org/10.1128/iai.00500-22
J Microbiol. 2023 Jan 31.

Bacterial Crosstalk via Antimicrobial Peptides on the Human Skin: Therapeutics from a Sustainable Perspective.

Seon Mi Lee, Hye Lim Keum, Woo Jun Sul.

  The skin's epidermis is an essential barrier as the first guard against invading pathogens, and physical protector from external injury. The skin microbiome, which consists of numerous bacteria, fungi, viruses, and archaea on the epidermis, play a key role in skin homeostasis. Antibiotics are a fast-acting and effective treatment method, however, antibiotic use is a nuisance that can disrupt skin homeostasis by eradicating beneficial bacteria along with the intended pathogens and cause antibiotic-resistant bacteria spread. Increased numbers of antimicrobial peptides (AMPs) derived from humans and bacteria have been reported, and their roles have been well defined. Recently, modulation of the skin microbiome with AMPs rather than artificially synthesized antibiotics has attracted the attention of researchers as many antibiotic-resistant strains make treatment mediation difficult in the context of ecological problems. Herein, we discuss the overall insights into the skin microbiome, including its regulation by different AMPs, as well as their composition and role in health and disease.

Keywords:  Antimicrobial peptides; Bacterial-bacterial interaction; Bacteriotherapy; Host-bacterial interaction; Skin microbiome

DOI:  https://doi.org/10.1007/s12275-022-00002-8
Front Immunol. 2022 ;13 1046472

Immunological consequences of microbiome-based therapeutics.

Md Zahidul Alam, Jeffrey R Maslanka, Michael C Abt.

  The complex network of microscopic organisms living on and within humans, collectively referred to as the microbiome, produce wide array of biologically active molecules that shape our health. Disruption of the microbiome is associated with susceptibility to a range of diseases such as cancer, diabetes, allergy, obesity, and infection. A new series of next-generation microbiome-based therapies are being developed to treat these diseases by transplanting bacteria or bacterial-derived byproducts into a diseased individual to reset the recipient's microbiome and restore health. Microbiome transplantation therapy is still in its early stages of being a routine treatment option and, with a few notable exceptions, has had limited success in clinical trials. In this review, we highlight the successes and challenges of implementing these therapies to treat disease with a focus on interactions between the immune system and microbiome-based therapeutics. The immune activation status of the microbiome transplant recipient prior to transplantation has an important role in supporting bacterial engraftment. Following engraftment, microbiome transplant derived signals can modulate immune function to ameliorate disease. As novel microbiome-based therapeutics are developed, consideration of how the transplants will interact with the immune system will be a key factor in determining whether the microbiome-based transplant elicits its intended therapeutic effect.

Keywords:  C. difficile; fecal microbiota transplantation; immune checkpoint inhibitors; live biotherapeutic products; microbiome-based therapeutic; mucosal immunity; probiotics; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2022.1046472
Front Cell Infect Microbiol. 2022 ;12 1060748

Rhinovirus increases Moraxella catarrhalis adhesion to the respiratory epithelium.

Eishika Dissanayake, Rebecca A Brockman-Schneider, Reed M Stubbendieck, Britney A Helling, Zhumin Zhang, Yury A Bochkov, Charmaine Kirkham, Timothy F Murphy, Carole Ober, Cameron R Currie, James E Gern.

  Rhinovirus causes many types of respiratory illnesses, ranging from minor colds to exacerbations of asthma. Moraxella catarrhalis is an opportunistic pathogen that is increased in abundance during rhinovirus illnesses and asthma exacerbations and is associated with increased severity of illness through mechanisms that are ill-defined. We used a co-infection model of human airway epithelium differentiated at the air-liquid interface to test the hypothesis that rhinovirus infection promotes M. catarrhalis adhesion and survival on the respiratory epithelium. Initial experiments showed that infection with M. catarrhalis alone did not damage the epithelium or induce cytokine production, but increased trans-epithelial electrical resistance, indicative of increased barrier function. In a co-infection model, infection with the more virulent rhinovirus-A and rhinovirus-C, but not the less virulent rhinovirus-B types, increased cell-associated M. catarrhalis. Immunofluorescent staining demonstrated that M. catarrhalis adhered to rhinovirus-infected ciliated epithelial cells and infected cells being extruded from the epithelium. Rhinovirus induced pronounced changes in gene expression and secretion of inflammatory cytokines. In contrast, M. catarrhalis caused minimal effects and did not enhance RV-induced responses. Our results indicate that rhinovirus-A or C infection increases M. catarrhalis survival and cell association while M. catarrhalis infection alone does not cause cytopathology or epithelial inflammation. Our findings suggest that rhinovirus and M. catarrhalis co-infection could promote epithelial damage and more severe illness by amplifying leukocyte inflammatory responses at the epithelial surface.

Keywords:  Moraxella catarrhalis; airway epithelium; asthma; co-infection; rhinovirus

DOI:  https://doi.org/10.3389/fcimb.2022.1060748
J Invest Dermatol. 2023 Feb 01. pii: S0022-202X(23)00070-2. [Epub ahead of print]

IL-17 signaling in keratinocytes orchestrates the defense against Staphylococcus aureus skin infection.

Sonja Moos, Tommy Regen, Florian Wanke, Yizhu Tian, Lucas Arendholz, Judith Hauptmann, André P Heinen, Lisa Bleul, Katharina Bier, Khalifa El Malki, Christoph Reinhardt, Immo Prinz, Andreas Diefenbach, Christiane Wolz, Birgit Schittek, Ari Waisman, Florian C Kurschus.

  Keratinocytes form the outer epithelial barrier of the body protecting against invading pathogens. Mice lacking the IL-17 receptor A (IL-17RA) or both IL-17A and IL-17F develop spontaneous Staphylococcus aureus (S. aureus) skin infections. We found a marked expansion of T17 cells, comprised of RORγt-expressing γδ T cells and TH17 cells in the skin-draining lymph nodes of these mice. Contradictory to previous suggestions, this expansion was not a result of a direct negative feedback loop, as we found no expansion of T17 cells in mice lacking IL-17-signaling specifically in T cells. Instead, we found that the T17 expansion depended on the microbiota and was observed only when keratinocytes were deficient for IL-17RA-signaling. Indeed, mice that lack IL-17RA only in keratinocytes showed an increased susceptibility to experimental epicutaneous infection with S. aureus together with an accumulation of IL-17A-producing γδ T cells. We conclude that deficiency of IL-17RA on keratinocytes leads to microbiota dysbiosis in the skin which triggers expansion of IL-17A-producing T cells. Our data show that keratinocytes are the primary target cells of IL-17A and IL-17F coordinating the defense against microbial invaders in the skin.

Keywords:  IL-17; S. aureus; T(H)17 cells; microbiota; γδ T cells

DOI:  https://doi.org/10.1016/j.jid.2023.01.016
mBio. 2023 Feb 01. e0355822

Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling.

Elizabeth V K Ledger, Andrew M Edwards.

  Almost all bactericidal drugs require bacterial replication and/or metabolic activity for their killing activity. When these processes are inhibited by bacteriostatic antibiotics, bacterial killing is significantly reduced. One notable exception is the lipopeptide antibiotic daptomycin, which has been reported to efficiently kill growth-arrested bacteria. However, these studies employed only short periods of growth arrest (<1 h), which may not fully represent the duration of growth arrest that can occur in vivo. We found that a growth inhibitory concentration of the protein synthesis inhibitor tetracycline led to a time-dependent induction of daptomycin tolerance in S. aureus, with an approximately 100,000-fold increase in survival after 16 h of growth arrest, relative to exponential-phase bacteria. Daptomycin tolerance required glucose and was associated with increased production of the cell wall polymers peptidoglycan and wall-teichoic acids. However, while the accumulation of peptidoglycan was required for daptomycin tolerance, only a low abundance of wall teichoic acid was necessary. Therefore, whereas tolerance to most antibiotics occurs passively due to a lack of metabolic activity and/or replication, daptomycin tolerance arises via active cell wall remodelling. IMPORTANCE Understanding why antibiotics sometimes fail to cure infections is fundamental to improving treatment outcomes. This is a major challenge when it comes to Staphylococcus aureus because this pathogen causes several different chronic or recurrent infections. Previous work has shown that a lack of replication, as often occurs during infection, makes bacteria tolerant of most bactericidal antibiotics. However, one antibiotic that has been reported to kill nonreplicating bacteria is daptomycin. In this work, we show that the growth arrest of S. aureus does in fact lead to daptomycin tolerance, but it requires time, nutrients, and biosynthetic pathways, making it distinct from other types of antibiotic tolerance that occur in nonreplicating bacteria.

Keywords:  MRSA; Staphylococcus aureus; antibiotic tolerance; daptomycin; growth arrest; peptidoglycan

DOI:  https://doi.org/10.1128/mbio.03558-22
Microbiol Spectr. 2023 Feb 01. e0367322

Oral Vaccination with Engineered Probiotic Limosilactobacillus reuteri Has Protective Effects against Localized and Systemic Staphylococcus aureus Infection.

Na Pan, Yang Liu, Haochi Zhang, Ying Xu, Xuemei Bao, Shouxin Sheng, Yanchen Liang, Bohui Liu, Yueqing Lyu, Haotian Li, Fangfei Ma, Haiting Pan, Xiao Wang.

  Staphylococcus aureus is a Gram-positive bacterium responsible for most hospital-acquired (nosocomial) and community-acquired infections worldwide. The only therapeutic strategy against S. aureus-induced infections, to date, is antibiotic treatment. A protective vaccine is urgently needed in view of the emergence of antibiotic-resistant strains associated with high-mortality cases; however, no such vaccine is currently available. In our previous work, the feasibility of implementing a Lactobacillus delivery system for development of S. aureus oral vaccine was first discussed. Here, we describe systematic screening and evaluation of protective effects of engineered Lactobacillus against S. aureus infection in terms of different delivery vehicle strains and S. aureus antigens and in localized and systemic infection models. Limosilactobacillus reuteri WXD171 was selected as the delivery vehicle strain based on its tolerance of the gastrointestinal environment, adhesion ability, and antimicrobial activities in vitro and in vivo. We designed, constructed, and evaluated engineered L. reuteri strains expressing various S. aureus antigens. Among these, engineered L. reuteri WXD171-IsdB displayed effective protection against S. aureus-induced localized infection (pneumonia and skin infection) and, furthermore, a substantial survival benefit in systemic infection (sepsis). WXD171-IsdB induced mucosal responses in gut-associated lymphoid tissues, as evidenced by increased production of secretory IgA and interleukin 17A (IL-17A) and proliferation of lymphocytes derived from Peyer's patches. The probiotic L. reuteri-based oral vaccine appears to have strong potential as a prophylactic agent against S. aureus infections. Our findings regarding utilization of Lactobacillus delivery system in S. aureus vaccine development support the usefulness of this live vaccination strategy and its potential application in next-generation vaccine development. IMPORTANCE We systematically screened and evaluated protective effects of engineered Lactobacillus against S. aureus infection in terms of differing delivery vehicle strains and S. aureus antigens and in localized and systemic infection models. Engineered L. reuteri was developed and showed strong protective effects against both types of S. aureus-induced infection. Our findings regarding the utilization of a Lactobacillus delivery system in S. aureus vaccine development support the usefulness of this live vaccination strategy and its potential application in next-generation vaccine development.

Keywords:  Lactobacillus; Staphylococcus aureus; mucosal delivery system; oral vaccine; probiotic

DOI:  https://doi.org/10.1128/spectrum.03673-22
J Invest Dermatol. 2023 Jan 31. pii: S0022-202X(23)00066-0. [Epub ahead of print]

Skin colonization with S. aureus can lead to increased NLRP1 inflammasome activation in patients with atopic dermatitis.

Helen Vaher, Kristiina Kingo, Peep Kolberg, Martin Pook, Liisi Raam, Anet Laanesoo, Anu Remm, Tanel Tenson, Kaur Alasoo, Ulrich Mrowietz, Stephan Weidinger, Külli Kingo, Ana Rebane.

  The role of NLRP1 inflammasome activation and subsequent production of IL-1 family cytokines in the development of atopic dermatitis (AD) is not clearly understood. S. aureus is known to be associated with increased mRNA levels of IL-1 family cytokines in the skin and more severe AD. In this study, the altered expression of IL-1 family cytokines and inflammasome-related genes was confirmed and positive relationship between mRNA levels of inflammasome sensor NLRP1 and IL1B or IL18 was determined. Enhanced expression of the NLRP1 and PYCARD proteins, and increased caspase-1 activity were detected in the skin of AD patients. The genetic association of IL18R1 and IL18RAP with AD was confirmed and the involvement of various immune cell types was predicted using published GWAS and eQTL datasets. In keratinocytes, the inoculation with S. aureus led to the increased secretion of IL-1β and IL-18, while siRNA silencing of NLRP1 inhibited the production of these cytokines. Our results together suggest that skin colonization with S. aureus may cause the activation of the NLRP1 inflammasome in keratinocytes, which leads to the secretion of IL-1β and IL-18 and thereby may contribute to the pathogenesis of AD, particularly in the presence of genetic variations in the IL-18 pathway.

Keywords:  Atopic dermatitis; Bacteria; Infection; Inflammation; Interleukins; Keratinocytes

DOI:  https://doi.org/10.1016/j.jid.2023.01.013