bims-bac4me 2024-05-12 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–05–12
33 papers selected by
Chun-Chi Chang, University Hospital Zurich

Impaired upper respiratory tract barrier function during postnatal development predisposes to invasive pneumococcal disease.
Maintenance of homeostasis by TLR4 ligands.
Inhaled antibiotics: A promising drug delivery strategies for efficient treatment of lower respiratory tract infections (LRTIs) associated with antibiotic resistant biofilm-dwelling and intracellular bacterial pathogens.
HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.
Navigating the crossroads: asthma, trained immunity, and infection susceptibility.
Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice.
Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.
The hidden functional diversity of macrophages.
Role of the intestinal microbiota in host defense against respiratory viral infections.
Inborn errors of immunity with susceptibility to S. aureus infections.
Development and establishment of oral microbiota in early life.
Scutellaria baicalensis water decoction ameliorates lower respiratory tract infection by modulating respiratory microbiota.
Bacteria-derived short-chain fatty acids as potential regulators of fungal commensalism and pathogenesis.
Oral administration of Lactobacillus delbrueckii subsp. lactis LDL557 attenuates airway inflammation and changes the gut microbiota in a Der p-sensitized mouse model of allergic asthma.
Triggering Toll-Like Receptor 5 signaling during pneumococcal superinfection prevents the selection of antibiotic resistance.
One health: Coming of age and antimicrobial resistance.
Gut dopamine kick: How gut microbes turn on host receptors to fight pathogens.
Exploring host-commensal-pathogen dynamics in cell line and organotypic human intestinal epithelial models.
Inflammatory Memory in Chronic Skin Disease.
ALOX15+ M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps.
Skin-associated Corynebacterium amycolatum shares cobamides.
Harnessing inter-kingdom metabolic disparities at the human-fungal interface for novel therapeutic approaches.
CpsA mediates infection of recruited lung myeloid cells by Mycobacterium tuberculosis.
Mechanisms of microbiota modulation: Implications for health, disease, and therapeutic interventions.
LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis.
Amino acid bites: Microbial snacking influences host metabolism.
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
Molecular commensalism: how oral corynebacteria and their extracellular membrane vesicles shape microbiome interactions.
Considering the host in host-pathogen interactions.
Mapping the Human Cell Surface Interactome: A Key to Decode Cell-to-Cell Communication.
Approach to the diagnosis and management of dysbiosis.
Immunosuppressive effects of morphine on macrophage polarization and function.
TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.

PLoS Pathog. 2024 May;20(5): e1012111

Impaired upper respiratory tract barrier function during postnatal development predisposes to invasive pneumococcal disease.

Kristen L Lokken-Toyli, Surya D Aggarwal, Gavyn Chern Wei Bee, Wouter A A de Steenhuijsen Piters, Cindy Wu, Kenny Zhi Ming Chen, Cynthia Loomis, Debby Bogaert, Jeffrey N Weiser.

Infants are highly susceptible to invasive respiratory and gastrointestinal infections. To elucidate the age-dependent mechanism(s) that drive bacterial spread from the mucosa, we developed an infant mouse model using the prevalent pediatric respiratory pathogen, Streptococcus pneumoniae (Spn). Despite similar upper respiratory tract (URT) colonization levels, the survival rate of Spn-infected infant mice was significantly decreased compared to adults and corresponded with Spn dissemination to the bloodstream. An increased rate of pneumococcal bacteremia in early life beyond the newborn period was attributed to increased bacterial translocation across the URT barrier. Bacterial dissemination in infant mice was independent of URT monocyte or neutrophil infiltration, phagocyte-derived ROS or RNS, inflammation mediated by toll-like receptor 2 or interleukin 1 receptor signaling, or the pore-forming toxin pneumolysin. Using molecular barcoding of Spn, we found that only a minority of bacterial clones in the nasopharynx disseminated to the blood in infant mice, indicating the absence of robust URT barrier breakdown. Rather, transcriptional profiling of the URT epithelium revealed a failure of infant mice to upregulate genes involved in the tight junction pathway. Expression of many such genes was also decreased in early life in humans. Infant mice also showed increased URT barrier permeability and delayed mucociliary clearance during the first two weeks of life, which corresponded with tighter attachment of bacteria to the respiratory epithelium. Together, these results demonstrate a window of vulnerability during postnatal development when altered mucosal barrier function facilitates bacterial dissemination.

DOI: https://doi.org/10.1371/journal.ppat.1012111
Front Immunol. 2024 ;15 1286270

Maintenance of homeostasis by TLR4 ligands.

Masataka Oda, Hirofumi Yamamoto, Takashige Kawakami.

  Immunotherapy is renowned for its capacity to elicit anti-infective and anti-cancer effects by harnessing immune responses to microbial components and bolstering innate healing mechanisms through a cascade of immunological reactions. Specifically, mammalian Toll-like receptors (TLRs) have been identified as key receptors responsible for detecting microbial components. The discovery of these mammalian Toll-like receptors has clarified antigen recognition by the innate immune system. It has furnished a molecular foundation for comprehending the interplay between innate immunity and its anti-tumor or anti-infective capabilities. Moreover, accumulating evidence highlights the crucial role of TLRs in maintaining tissue homeostasis. It has also become evident that TLR-expressing macrophages play a central role in immunity by participating in the clearance of foreign substances, tissue repair, and the establishment of new tissue. This macrophage network, centered on macrophages, significantly contributes to innate healing. This review will primarily delve into innate immunity, specifically focusing on substances targeting TLR4.

Keywords:  TLR4 ligands; innate immunity; macrophage; macrophage network; self-healing ability

DOI:  https://doi.org/10.3389/fimmu.2024.1286270
Respir Med. 2024 May 08. pii: S0954-6111(24)00135-5. [Epub ahead of print] 107661

Inhaled antibiotics: A promising drug delivery strategies for efficient treatment of lower respiratory tract infections (LRTIs) associated with antibiotic resistant biofilm-dwelling and intracellular bacterial pathogens.

Nazrul Islam, David Reid.

  Antibiotic-resistant bacteria associated with LRTIs are frequently associated with inefficient treatment outcomes. Antibiotic-resistant Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus, infections are strongly associated with pulmonary exacerbations and require frequent hospital admissions, usually following failed management in the community. These bacteria are difficult to treat as they demonstrate multiple adaptational mechanisms including biofilm formation to resist antibiotic threats. Currently, many patients with the genetic disease cystic fibrosis (CF), non-CF bronchiectasis (NCFB) and chronic obstructive pulmonary disease (COPD) experience exacerbations of their lung disease and require high doses of systemically administered antibiotics to achieve meaningful clinical effects, but even with high systemic doses penetration of antibiotic into the site of infection within the lung is suboptimal. Pulmonary drug delivery technology that reliably deliver antibacterials directly into the infected cells of the lungs and penetrate bacterial biofilms to provide therapeutic doses with a greatly reduced risk of systemic adverse effects. Inhaled liposomal-packaged antibiotic with biofilm-dissolving drugs offer the opportunity for targeted, and highly effective antibacterial therapeutics in the lungs. Although the challenges with development of some inhaled antibiotics and their clinicals trials have been studied; however, only few inhaled products are available on market. This review addresses the current treatment challenges of antibiotic-resistant bacteria in the lung with some clinical outcomes and provides future directions with innovative ideas on new inhaled formulations and delivery technology that promise enhanced killing of antibiotic-resistant biofilm-dwelling bacteria.

Keywords:  antibiotic; bacteria; biofilm; lower respiratory tract infections (LRTIs); nanoparticles; pulmonary drug delivery; resistant bacteria

DOI:  https://doi.org/10.1016/j.rmed.2024.107661
Clin Exp Pharmacol Physiol. 2024 Jun;51(6): e13866

HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.

Maimaitiaili Yimiti, Xuefeng Fei, Hao Yang, Xiaobao Yang, Shuhui Li, Huxidanmu Tuoheniyazi, Danping Liu, Junrui Ma, Jialing Xie, Juanjuan Zheng, Zhen Song, Qingtian Li, Dakang Xu, Yanan Zhao, Zhidong Gu.

  Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

Keywords:  HDAC6; ROS; Staphylococcus aureus; macrophage; tubastatin A

DOI:  https://doi.org/10.1111/1440-1681.13866
Expert Rev Clin Immunol. 2024 May 09. 1-3

Navigating the crossroads: asthma, trained immunity, and infection susceptibility.

Ahmad Z Al Meslamani, Eman Merghani Ali.



Keywords:  Asthma; infections; microbiome; precision medicine; trained immunity

DOI:  https://doi.org/10.1080/1744666X.2024.2353743
Int J Biol Sci. 2024 ;20(7): 2555-2575

Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice.

Bingsheng Yang, Wen Shu, Jin Hu, Zhongwen Wang, Jichang Wu, Jianwen Su, Jianye Tan, Bin Yu, Xianrong Zhang.

  Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.

Keywords:  Lipid peroxidation; Macrophage; Osteomyelitis; PD-L1; SLC7A11; Staphylococcus aureus

DOI:  https://doi.org/10.7150/ijbs.93592
Nat Commun. 2024 May 09. 15(1): 3926

Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.

Tingting Zhou, Norma V Solis, Michaela Marshall, Qing Yao, Rachel Garleb, Mengli Yang, Eric Pearlman, Scott G Filler, Haoping Liu.

Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.

DOI: https://doi.org/10.1038/s41467-024-48093-8
Nat Immunol. 2024 May 08.

The hidden functional diversity of macrophages.

DOI: https://doi.org/10.1038/s41590-024-01832-x
Curr Opin Virol. 2024 May 07. pii: S1879-6257(24)00024-5. [Epub ahead of print]66 101410

Role of the intestinal microbiota in host defense against respiratory viral infections.

Idia Boncheva, Johanne Poudrier, Emilia L Falcone.

Viral infections, including those affecting the respiratory tract, can alter the composition of the intestinal microbiota, which, in turn, can significantly influence both innate and adaptive immune responses, resulting in either enhanced pathogen clearance or exacerbation of the infection, possibly leading to inflammatory complications. A deeper understanding of the interplay between the intestinal microbiota and host immune responses in the context of respiratory viral infections (i.e. the gut-lung axis) is necessary to develop new treatments. This review highlights key mechanisms by which the intestinal microbiota, including its metabolites, can act locally or at distant organs to combat respiratory viruses. Therapeutics aimed at harnessing the microbiota to prevent and/or help treat respiratory viral infections represent a promising avenue for future investigation.

DOI: https://doi.org/10.1016/j.coviro.2024.101410
Front Pediatr. 2024 ;12 1389650

Inborn errors of immunity with susceptibility to S. aureus infections.

Hannah Kurz, Kai Lehmberg, Susan Farmand.

  Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

Keywords:  IL-6 deficiency; S. aureus; STAT3 deficiency; chronic granulomatous disease (CGD); immunodeficiency; inborn errors of immunity (IEI); neutropenia; neutrophil dysfunction

DOI:  https://doi.org/10.3389/fped.2024.1389650
J Oral Biosci. 2024 May 02. pii: S1349-0079(24)00084-7. [Epub ahead of print]

Development and establishment of oral microbiota in early life.

Shinya Kageyama, Toru Takeshita.

   BACKGROUND: The oral microbiota has recently attracted attention owing to its association with oral and systemic diseases. Accordingly, gaining an understanding of oral microbiota development and the factors influencing it can contribute to preventing the establishment of dysbiotic oral microbiota and, eventually, oral microbiota-related diseases.
HIGHLIGHT: In this review, we highlight the results of a longitudinal project focusing on oral microbiota development during early life. At 4 months of age, the oral microbiota of infants was found to differ considerably from the maternal oral microbiota, even though infants acquire oral bacteria from their mothers. At 18 months, although the infant microbiota is still not completely comparable with that of adults, from 4 to 18 months, there is a rapid phase of development, during which the microbial composition undergoes considerable change to a profile more similar to that in adults. During this development, the infant oral microbiota converges into two different profiles with adult-like traits, namely, Streptococcus salivarius- and Neisseria-dominant profiles. This divergence is strongly influenced by dietary habits, with a frequent intake of sweetened beverages being associated with an S. salivarius-dominant profile, which is suspected to be implicated in oral and systemic diseases.
CONCLUSION: The foundation of the adult oral microbiota may be established by 18 months of age, and the developmental period from 4 to 18 months may be an appropriate period during which to modify the microbial balance to obtain a desirable healthy state. In particular, dietary habits during this period warrant close attention.

Keywords:  16S rRNA; Baby; Infant; Microbiome

DOI:  https://doi.org/10.1016/j.job.2024.05.001
Phytomedicine. 2024 May 04. pii: S0944-7113(24)00365-9. [Epub ahead of print]129 155706

Scutellaria baicalensis water decoction ameliorates lower respiratory tract infection by modulating respiratory microbiota.

Yanqin Luo, Bo Lin, Peng Yu, Di Zhang, Yingfan Hu, Xianli Meng, Li Xiang.

   BACKGROUND: The pathogenesis of lower respiratory tract infections (LRTIs) has been demonstrated to be strongly associated with dysbiosis of respiratory microbiota. Scutellaria baicalensis, a traditional Chinese medicine, is widely used to treat respiratory infections. However, whether the therapeutic effect of S. baicalensis on LRTIs depends upon respiratory microbiota regulation is largely unclear.
PURPOSE: To investigate the potential effect and mechanism of S. baicalensis on the respiratory microbiota of LRTI mice.
METHODS: A mouse model of LRTI was established using Klebsiella pneumoniae or Streptococcus pneumoniae. Antibiotic treatment was administered, and transplantation of respiratory microbiota was performed to deplete the respiratory microbiota of mice and recover the destroyed microbial community, respectively. High-performance liquid chromatography (HPLC) was used to determine and quantify the chemical components of S. baicalensis water decoction (SBWD). Pathological changes in lung tissues and the expressions of serum inflammatory cytokines, including interleukin-17A (IL-17A), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were determined by hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA), respectively. Quantitative real-time PCR (qRT-PCR) analysis was performed to detect the mRNA expression of GM-CSF. Metagenomic sequencing was performed to evaluate the effect of SBWD on the composition and function of the respiratory microbiota in LRTI mice.
RESULTS: Seven main components, including scutellarin, baicalin, oroxylin A-7-O-β-d-glucuronide, wogonoside, baicalein, wogonin, and oroxylin A, were identified and their levels in SBWD were quantified. SBWD ameliorated pulmonary pathological injury and inflammatory responses in K. pneumoniae and S. pneumoniae-induced LRTI mice, as evidenced by the dose-dependent reductions in the levels of serum inflammatory cytokines, IL-6 and TNF-α. SBWD may exert a bidirectional regulatory effect on the host innate immune responses in LRTI mice and regulate the expressions of IL-17A and GM-CSF in a microbiota-dependent manner. K. pneumoniae infection but not S. pneumoniae infection led to dysbiosis in the respiratory microbiota, evident through disturbances in the taxonomic composition characterized by bacterial enrichment, including Proteobacteria, Enterobacteriaceae, and Klebsiella. K. pneumoniae and S. pneumoniae infection altered the bacterial functional profile of the respiratory microbiota, as indicated by increases in lipopolysaccharide biosynthesis, metabolic pathways, and carbohydrate metabolism. SBWD had a certain trend on the regulation of compositional disorders in the respiratory flora and modulated partial microbial functions embracing carbohydrate metabolism in K. pneumoniae-induced LRTI mice.
CONCLUSION: SBWD may exert an anti-infection effect on LRTI by targeting IL-17A and GM-CSF through respiratory microbiota regulation. The mechanism of S. baicalensis action on respiratory microbiota in LRTI treatment merits further investigation.

Keywords:  Klebsiella pneumoniae; Lower respiratory tract infection; Respiratory microbiota; Scutellaria baicalensis; Streptococcus pneumoniae

DOI:  https://doi.org/10.1016/j.phymed.2024.155706
Trends Microbiol. 2024 May 09. pii: S0966-842X(24)00089-1. [Epub ahead of print]

Bacteria-derived short-chain fatty acids as potential regulators of fungal commensalism and pathogenesis.

Christopher McCrory, Megan Lenardon, Ana Traven.

  The human gastrointestinal microbiome encompasses bacteria, fungi, and viruses forming complex bionetworks which, for organismal health, must be in a state of homeostasis. An important homeostatic mechanism derives from microbial competition, which maintains the relative abundance of microbial species in a healthy balance. Microbes compete for nutrients and secrete metabolites that inhibit other microbes. Short-chain fatty acids (SCFAs) are one such class of metabolites made by gut bacteria to very high levels. SCFAs are metabolised by microbes and host cells and have multiple roles in regulating cell physiology. Here, we review the mechanisms by which SCFAs regulate the fungal gut commensal Candida albicans. We discuss SCFA's ability to inhibit fungal growth, limit invasive behaviours and modulate cell surface antigens recognised by immune cells. We review the mechanisms underlying these roles: regulation of gene expression, metabolism, signalling and SCFA-driven post-translational protein modifications by acylation, which contribute to changes in acylome dynamics of C. albicans with potentially large consequences for cell physiology. Given that the gut mycobiome is a reservoir for systemic disease and has also been implicated in inflammatory bowel disease, understanding the mechanisms by which bacterial metabolites, such as SCFAs, control the mycobiome might provide therapeutic avenues.

Keywords:  Candida albicans–bacteria interactions; gut microbiome; mycobiome; protein acylations; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.tim.2024.04.004
Asian Pac J Allergy Immunol. 2024 May 06.

Oral administration of Lactobacillus delbrueckii subsp. lactis LDL557 attenuates airway inflammation and changes the gut microbiota in a Der p-sensitized mouse model of allergic asthma.

Pei-Chi Chen, Miao-Hsi Hsieh, Wei-Leng Chen, Yu-Pu Hsia, Wen-Shuo Kuo, Lawrence Shih-Hsin Wu, Ting Fan Shulhn-Der Wang, Xiao-Yu Liu, Jiu-Yao Wang, Hui-Fang Kao.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children in developed countries. Although probiotics have shown promise as adjuvant treatments for AD, their mechanisms are not well understood.
OBJECTIVE: Building upon our previous studies, we investigated whether Lactobacillus gasseri and its moonlighting glyceraldehyde 3-phosphate dehydrogenase (GAPDH), namely LGp40, could be beneficial in AD management.
METHODS: In AD mouse models (SKH and C57BL/6J mice) with ovalbumin (OVA) and Dermatophagoides pteronyssinus (Der p) allergens, aligning with the "outside-in" and "inside-out" hypotheses, we administered L. gasseri orally and LGp40 intraperitoneally to investigate their protective effects. The evaluation involved measuring physiological, pathological, and immune function parameters. To delve deeper into the detailed mechanism of LGp40 protection in AD, additional assays were conducted using human skin keratinocytes (HaCaT) and monocytes (THP1) cell lines.
RESULTS: L. gasseri and LGp40 enhanced skin barrier function and increased skin moisture retention. They also led to reduced infiltration of Langerhans cells in the dermis and mitigated skewed Th2 and Th17 immune responses. Moreover, LGp40 inhibited allergen-induced keratinocyte apoptosis through the blockade of the caspase-3 cascade and reduced the NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. These inhibitions were achieved through the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway.
CONCLUSION: The results of this study provide a novel insight into the mechanism of action of probiotics in the prevention and treatment for allergic disorders through the moonlighting GAPDH protein.

DOI: https://doi.org/10.12932/AP-200823-1672
J Infect Dis. 2024 May 08. pii: jiae239. [Epub ahead of print]

Triggering Toll-Like Receptor 5 signaling during pneumococcal superinfection prevents the selection of antibiotic resistance.

Charlotte Costa, Jean-Claude Sirard, Paddy S Gibson, Jan-Willem Veening, Erida Gjini, Mara Baldry.

  Toll-like receptor 5 (TLR5) signaling plays a key role in antibacterial defenses. We previously showed that respiratory administration of flagellin, a potent TLR5 agonist, in combination with amoxicillin improves the treatment of primary pneumonia or superinfection caused by amoxicillin-sensitive or -resistant Streptococcus pneumoniae. Here, the impact of adjunct flagellin therapy on antibiotic dose/regimen and the selection of antibiotic-resistant S. pneumoniae was investigated using superinfection with isogenic antibiotic-sensitive and -resistant bacteria and population dynamics analysis. Our findings demonstrate that flagellin allows for a 200-fold reduction in the antibiotic dose, achieving the same therapeutic effect observed with antibiotic alone. Adjunct treatment also reduced the selection of antibiotic-resistant bacteria in contrast to the antibiotic monotherapy. Finally, we developed a mathematical model that captured the population dynamics and estimated a 20-fold enhancement immune-modulatory factor on bacterial clearance. This work paves the way for the development of host-directed therapy and refinement of treatment by modeling.

Keywords:   Streptococcus pneumoniae ; Flagellin; Toll-like receptor 5; airways; antibiotic resistance; infection dynamics; innate immunity; modelling

DOI:  https://doi.org/10.1093/infdis/jiae239
Epidemiol Infect. 2024 May 07. 152 e71

One health: Coming of age and antimicrobial resistance.

Dame Sally C Davies.

DOI: https://doi.org/10.1017/S0950268824000529
Cell Host Microbe. 2024 May 08. pii: S1931-3128(24)00131-8. [Epub ahead of print]32(5): 623-624

Gut dopamine kick: How gut microbes turn on host receptors to fight pathogens.

Eran Gutman, Yael Litvak.

Common nutrients in our diet often affect our health through unexpected mechanisms. In a recent issue of Nature, Scott et al. show gut microbes convert dietary tryptophan into metabolites activating intestinal dopamine receptors, which can block attachment of bacterial pathogens to host cells.

DOI: https://doi.org/10.1016/j.chom.2024.04.011
iScience. 2024 May 17. 27(5): 109771

Exploring host-commensal-pathogen dynamics in cell line and organotypic human intestinal epithelial models.

Nening M Nanlohy, Nina Johannesson, Lucas Wijnands, Laura Arroyo, Jelle de Wit, Gerco den Hartog, Katja C Wolthers, Adithya Sridhar, Susana Fuentes.

  Host and microbiome intricately interact in the ecosystem of the human digestive tract, playing a crucial role in our health. These interactions can initiate immune responses in the epithelial cells, which, in turn, activate downstream responses in other immune cells. Here, we used a CaCo-2 and a human intestinal enteroid (HIE) model to explore epithelial responses to both commensal and pathogenic bacteria, individually and combined. CaCo-2 cells were co-cultured with peripheral blood mononuclear cells, revealing downstream activation of immune cells. While both systems showed comparable cytokine profiles, they differed in their responses to the different bacteria, with the organoid system being more representative of responses observed in humans. We provide evidence of the pro-inflammatory responses associated with these bacteria. These models contribute to a deeper understanding of the interactions between the microbiota, intestinal epithelium, and immune cells in the gut, promoting advances in the field of host-microbe interactions.

Keywords:  Cell biology; Microbiology; Microbiome

DOI:  https://doi.org/10.1016/j.isci.2024.109771
JID Innov. 2024 May;4(3): 100277

Inflammatory Memory in Chronic Skin Disease.

Joseph A Daccache, Shruti Naik.

  Inflammation is a hallmark of remitting-relapsing dermatological diseases. Although a large emphasis has been placed on adaptive immune cells as mediators of relapse, evidence in epithelial and innate immune biology suggests that disease memory is widespread. In this study, we bring to the fore the concept of inflammatory memory or nonspecific training of long-lived cells in the skin, highlighting the epigenetic and other mechanisms that propagate memory at the cellular level. We place these findings in the context of psoriasis, a prototypic flaring disease known to have localized memory, and underscore the importance of targeting memory to limit disease flares.

Keywords:  Epigenetics; Inflammatory memory; Psoriasis

DOI:  https://doi.org/10.1016/j.xjidi.2024.100277
J Allergy Clin Immunol. 2024 May 03. pii: S0091-6749(24)00452-4. [Epub ahead of print]

ALOX15+ M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps.

Chang Liu, Kanghua Wang, Wenqin Liu, Jinxiu Zhang, Yunping Fan, Yueqi Sun.

   BACKGROUND: Epithelial remodeling is a prominent feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP), and infiltration of M2 macrophages plays a pivotal role in the pathogenesis of eCRSwNP, but the underlying mechanisms remain undefined.
OBJECTIVE: We aimed to investigate the role of ALOX15+ M2 macrophages in the epithelial remodeling of eCRSwNP.
METHODS: Digital spatial transcriptome and single-cell sequencing analyses were used to characterize the epithelial remodeling and cellular infiltrate in eCRSwNP. Hematoxylin and eosin staining, immunohistochemical and immunofluorescent staining were used to explore the relationship between ALOX15+ M2 (CD68+CD163+) macrophages and epithelial remodeling. A co-culture system of primary human nasal epithelial cells (hNECs) and the macrophage cell line THP-1 was used to determine the underlying mechanisms.
RESULTS: Spatial transcriptomics analysis showed that upregulation of epithelial remodeling-related genes, such as VIM and MMP10, and enrichment of epithelial-mesenchymal transition (EMT)-related pathways, in the epithelial areas in eCRSwNP, with more abundance of epithelial basal, goblet and glandular cells. Single-cell analysis identified ALOX15+, rather ALOX15-, M2 macrophages were specifically highly expressed in eCRSwNP. CRSwNP with high ALOX15+ M2THP-1-IL-4+IL-13 macrophages had more obvious epithelial remodeling features and increased genes associated with epithelial remodeling and integrity of epithelial morphology versus that with low ALOX15+ M2THP-1-IL-4+IL-13 macrophages. IL-4/13-polarized M2THP-1-IL-4+IL-13 macrophages upregulated expressions of EMT-related genes in hNECs, including VIM, TWIST1, Snail, and ZEB1. ALOX15 inhibition in M2THP-1-IL-4+IL-13 macrophages resulted in reduction of the EMT-related transcripts in hNECs. Blocking CCL13 signaling inhibited M2THP-1-IL-4+IL-13 macrophage-induced EMT alteration in hNECs.
CONCLUSION: ALOX15+ M2 macrophages are specifically increased in eCRSwNP and may contribute to the pathogenesis of epithelial remodeling via production of CCL13.

Keywords:  15-lipoxygenase-1; epithelial remodeling; macrophage; nasal polyps; rhinosinusitis

DOI:  https://doi.org/10.1016/j.jaci.2024.04.019
bioRxiv. 2024 Apr 28. pii: 2024.04.28.591522. [Epub ahead of print]

Skin-associated Corynebacterium amycolatum shares cobamides.

Mary Hannah Swaney, Nicola Henriquez, Tracey Campbell, Jo Handelsman, Lindsay Kalan.

The underlying interactions that occur to maintain skin microbiome composition, function, and overall skin health are largely unknown. Often, these types of interactions are mediated by microbial metabolites. Cobamides, the vitamin B12 family of cofactors, are essential for metabolism in many bacteria, but are only synthesized by a small fraction of prokaryotes, including certain skin-associated species. Therefore, we hypothesize that cobamide sharing mediates skin community dynamics. Preliminary work predicts that several skin-associated Corynebacterium species encode de novo cobamide biosynthesis and that their abundance is associated with skin microbiome diversity. Here, we show that commensal Corynebacterium amycolatum produces cobamides and that this synthesis can be tuned by cobalt limitation. To demonstrate cobamide sharing by C. amycolatum, we employed a co-culture assay using an E. coli cobamide auxotroph and show that C. amycolatum produces sufficient cobamides to support E. coli growth, both in liquid co-culture and when separated spatially on solid medium. We also generated a C. amycolatum non-cobamide-producing strain (cob-) using UV mutagenesis that contains mutated cobamide biosynthesis genes cobK and cobO and confirm that disruption of cobamide biosynthesis abolishes support of E. coli growth through cobamide sharing. Our study provides a unique model to study metabolite sharing by microorganisms, which will be critical for understanding the fundamental interactions that occur within complex microbiomes and for developing approaches to target the human microbiota for health advances.

DOI: https://doi.org/10.1101/2024.04.28.591522
Front Mol Biosci. 2024 ;11 1386598

Harnessing inter-kingdom metabolic disparities at the human-fungal interface for novel therapeutic approaches.

Claudio Costantini, Marilena Pariano, Matteo Puccetti, Stefano Giovagnoli, Gioena Pampalone, Mirco Dindo, Barbara Cellini, Luigina Romani.

  Humans interact with a multitude of microorganisms in various ecological relationships, ranging from commensalism to pathogenicity. The same applies to fungi, long recognized for their pathogenic roles in infection-such as in invasive fungal diseases caused, among others, by Aspergillus fumigatus and Candida spp.-and, more recently, for their beneficial activities as an integral part of the microbiota. Indeed, alterations in the fungal component of the microbiota, or mycobiota, have been associated with inflammatory, infectious and metabolic diseases, and cancer. Whether acting as opportunistic pathogens or symbiotic commensals, fungi possess a complex enzymatic repertoire that intertwines with that of the host. In this metabolic cross-talk, fungal enzymes may be unique, thus providing novel metabolic opportunities to the host, or, conversely, produce toxic metabolites. Indeed, administration of fungal probiotics and fungi-derived products may be beneficial in inflammatory and infectious diseases, but fungi may also produce a plethora of toxic secondary metabolites, collectively known as mycotoxins. Fungal enzymes may also be homologues to human enzymes, but nevertheless embedded in fungal-specific metabolic networks, determined by all the interconnected enzymes and molecules, quantitatively and qualitatively specific to the network, such that the activity and metabolic effects of each enzyme remain unique to fungi. In this Opinion, we explore the concept that targeting this fungal metabolic unicity, either in opportunistic pathogens or commensals, may be exploited to develop novel therapeutic strategies. In doing so, we present our recent experience in different pathological settings that ultimately converge on relevant trans-kingdom metabolic differences.

Keywords:  functional biochemistry; fungal infections; inflammation; metabolic network; mycobiota

DOI:  https://doi.org/10.3389/fmolb.2024.1386598
Cell Rep. 2024 May 09. pii: S2211-1247(24)00529-1. [Epub ahead of print]43(5): 114201

CpsA mediates infection of recruited lung myeloid cells by Mycobacterium tuberculosis.

Steven J Grigsby, G V R Krishna Prasad, Joshua B Wallach, Ekansh Mittal, Fong-Fu Hsu, Dirk Schnappinger, Jennifer A Philips.

DOI: https://doi.org/10.1016/j.celrep.2024.114201
Medicine (Baltimore). 2024 May 10. 103(19): e38088

Mechanisms of microbiota modulation: Implications for health, disease, and therapeutic interventions.

Okechukwu Paul-Chima Ugwu, Esther Ugo Alum, Michael Ben Okon, Emmanuel I Obeagu.

Microbiota modulation, the intentional change in the structure and function of the microbial community, is an emerging trajectory that holds the promise to mitigate an infinite number of health issues. The present review illustrates the underlying principles of microbiota modulation and the various applications of this fundamental process to human health, healthcare management, and pharmacologic interventions. Different strategies, directing on dietary interventions, fecal microbiota transplantation, treatment with antibiotics, bacteriophages, microbiome engineering, and modulation of the immune system, are described in detail. This therapeutic implication is reflected in clinical applications to gastrointestinal disorders and immune-mediated diseases for microbiota-modulating agents. In addition to this, the review outlines the challenges of translating researched outcomes into clinical practice to consider safety and provides insights into future research directions of this rapidly developing area.

DOI: https://doi.org/10.1097/MD.0000000000038088
Cell Mol Life Sci. 2024 May 06. 81(1): 206

LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis.

Jinhua Feng, Han Zhong, Shuya Mei, Ri Tang, Yang Zhou, Shunpeng Xing, Yuan Gao, Qiaoyi Xu, Zhengyu He.

  The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.

Keywords:  Epithelial-mesenchymal transformation; Lactate; Lipopolysaccharide; Monocarboxylate transporter-1; Pulmonary fibrosis

DOI:  https://doi.org/10.1007/s00018-024-05242-y
Cell Host Microbe. 2024 May 08. pii: S1931-3128(24)00120-3. [Epub ahead of print]32(5): 630-632

Amino acid bites: Microbial snacking influences host metabolism.

Amélie Joly, Filipe De Vadder.

The gut microbiota has the capacity to metabolize food-derived molecules. In this issue of Cell Host & Microbe, Li et al. explore how some bacterial species of the gut microbiota can deplete amino acids in the gut lumen, modulating the amino acid landscape and energy metabolism of the host.

DOI: https://doi.org/10.1016/j.chom.2024.04.003
bioRxiv. 2024 Apr 28. pii: 2024.04.25.591150. [Epub ahead of print]

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.
SUMMARY: Small molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.

DOI: https://doi.org/10.1101/2024.04.25.591150
Front Oral Health. 2024 ;5 1410786

Molecular commensalism: how oral corynebacteria and their extracellular membrane vesicles shape microbiome interactions.

Jens Kreth, Emily Helliwell, Puthayalai Treerat, Justin Merritt.

  Historically, the study of microbe-associated diseases has focused primarily on pathogens, guided by Koch's postulates. This pathogen-centric view has provided a mechanistic understanding of disease etiology and microbial pathogenesis. However, next-generation sequencing approaches have revealed a far more nuanced view of the roles various microbes play in disease, highlighting the importance of microbial diversity beyond individual pathogens. This broader perspective acknowledges the roles of host and microbial communities in disease development and resistance. In particular, the concept of dysbiosis, especially within the oral cavity, has gained attention for explaining the emergence of complex polymicrobial diseases. Such diseases often stem from resident microbes rather than foreign pathogens, complicating their treatment and even clouding our understanding of disease etiology. Oral health is maintained through a delicate balance between commensal microbes and the host, with diseases like caries and periodontal disease arising from pathogenic perturbations of this balance. Commensal microbes, such as certain streptococci and Corynebacterium spp., play crucial roles in maintaining oral health through mechanisms involving hydrogen peroxide production and membrane vesicle secretion, which can inhibit pathogenic species and modulate host immune responses. Recent research focused upon the mechanisms of molecular commensalism has expanded our understanding of these key functions of the commensal microbiome, demonstrating their central role in promoting oral health and preventing disease. These abilities represent a largely untapped reservoir of potential innovative strategies for disease prevention and management, emphasizing the need to bolster a symbiotic microbiome that inherently suppresses pathogenesis.

Keywords:  biofilm; commensalism; corynebacteria; oral-general health; streptococci

DOI:  https://doi.org/10.3389/froh.2024.1410786
Nat Microbiol. 2024 May;9(5): 1149

Considering the host in host-pathogen interactions.

DOI: https://doi.org/10.1038/s41564-024-01708-8
Annu Rev Biomed Data Sci. 2024 May 09.

Mapping the Human Cell Surface Interactome: A Key to Decode Cell-to-Cell Communication.

Jarrod Shilts, Gavin J Wright.

Proteins on the surfaces of cells serve as physical connection points to bridge one cell with another, enabling direct communication between cells and cohesive structure. As biomedical research makes the leap from characterizing individual cells toward understanding the multicellular organization of the human body, the binding interactions between molecules on the surfaces of cells are foundational both for computational models and for clinical efforts to exploit these influential receptor pathways. To achieve this grander vision, we must assemble the full interactome of ways surface proteins can link together. This review investigates how close we are to knowing the human cell surface protein interactome. We summarize the current state of databases and systematic technologies to assemble surface protein interactomes, while highlighting substantial gaps that remain. We aim for this to serve as a road map for eventually building a more robust picture of the human cell surface protein interactome.

DOI: https://doi.org/10.1146/annurev-biodatasci-102523-103821
Front Nutr. 2024 ;11 1330903

Approach to the diagnosis and management of dysbiosis.

Kannayiram Alagiakrishnan, Joao Morgadinho, Tyler Halverson.

  All microorganisms like bacteria, viruses and fungi that reside within a host environment are considered a microbiome. The number of bacteria almost equal that of human cells, however, the genome of these bacteria may be almost 100 times larger than the human genome. Every aspect of the physiology and health can be influenced by the microbiome living in various parts of our body. Any imbalance in the microbiome composition or function is seen as dysbiosis. Different types of dysbiosis are seen and the corresponding symptoms depend on the site of microbial imbalance. The contribution of the intestinal and extra-intestinal microbiota to influence systemic activities is through interplay between different axes. Whole body dysbiosis is a complex process involving gut microbiome and non-gut related microbiome. It is still at the stage of infancy and has not yet been fully understood. Dysbiosis can be influenced by genetic factors, lifestyle habits, diet including ultra-processed foods and food additives, as well as medications. Dysbiosis has been associated with many systemic diseases and cannot be diagnosed through standard blood tests or investigations. Microbiota derived metabolites can be analyzed and can be useful in the management of dysbiosis. Whole body dysbiosis can be addressed by altering lifestyle factors, proper diet and microbial modulation. The effect of these interventions in humans depends on the beneficial microbiome alteration mostly based on animal studies with evolving evidence from human studies. There is tremendous potential for the human microbiome in the diagnosis, treatment, and prognosis of diseases, as well as, for the monitoring of health and disease in humans. Whole body system-based approach to the diagnosis of dysbiosis is better than a pure taxonomic approach. Whole body dysbiosis could be a new therapeutic target in the management of various health conditions.

Keywords:  dysbiosis; gut biotics; microbiome; microbiota; virtual organ

DOI:  https://doi.org/10.3389/fnut.2024.1330903
Eur J Pharmacol. 2024 May 08. pii: S0014-2999(24)00325-X. [Epub ahead of print] 176637

Immunosuppressive effects of morphine on macrophage polarization and function.

Jonaid Ahmad Malik, Mohammad Affan Khan, Taruna Lamba, Mohammad Adeel Zafar, Sidhanta Nanda, Mohammad Owais, Javed N Agrewala.

  Macrophages play a pivotal role in safeguarding against a broad spectrum of infections, from viral, bacterial, and fungal to parasitic threats and contributing to the immune defense against cancer. While morphine's immunosuppressive effects on immune cells are extensively documented, a significant knowledge gap exists regarding its influence on macrophage polarization and differentiation. Hence, we conducted a study that unveils that prior exposure to morphine significantly impedes the differentiation of bone marrow cells into macrophages. Furthermore, the polarization of these macrophages toward the M1 phenotype under M1-inducing conditions experiences substantial impairment, as evidenced by the diminished expression of CD80, CD86, CD40, iNOS, and MHCII. This correlates with reduced expression of M1 phenotypical markers such as iNOS, IL-1β, and IL-6, accompanied by noticeable morphological, size, and phagocytic alterations. Further, we also observed that morphine affected M2 macrophages. These findings emphasize the necessity for a more comprehensive understanding of the impact of morphine on compromising macrophage function and its potential ramifications for therapeutic approaches.

Keywords:  M1 macrophage; M2 macrophage; Morphine; antigen uptake; immunosuppression

DOI:  https://doi.org/10.1016/j.ejphar.2024.176637
bioRxiv. 2024 Apr 01. pii: 2024.04.01.587519. [Epub ahead of print]

TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.

Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Anthony J St Leger, Rachel R Caspi.

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis ( C. mast ) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast -responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.
Summary: The ocular commensal Corynebacterium mastitidis ( C. mast ) induces the IL-17 responses from γδ T cells by activating TLR2 signaling. γδ T cell-intrinsic TLR2 stimulation promotes fatty acid oxidation and increases IL-17A transcription, favoring IL-17A responses.
Highlights: (1) TLR2-deficient mice exhibit reduced γδ T cell responses to ocular commensal bacteria.(2) γδ T cell-intrinsic TLR2 deficiency causes defects of fatty acid oxidation and IL-17A production in a γδ subset-specific manner.(3) The transcription factor, IκBζ is upregulated by TLR2 stimulation and supports γδ IL-17A production through fatty acid oxidation.

DOI: https://doi.org/10.1101/2024.04.01.587519