{"title":"The bacterial defense system MADS interacts with CRISPR-Cas to limit phage infection and escape","authors":"","doi":"10.1016/j.chom.2024.07.005","DOIUrl":"https://doi.org/10.1016/j.chom.2024.07.005","url":null,"abstract":"<p>The constant arms race between bacteria and their parasites has resulted in a large diversity of bacterial defenses, with many bacteria carrying multiple systems. Here, we report the discovery of a phylogenetically widespread defense system, coined methylation-associated defense system (MADS), which is distributed across gram-positive and gram-negative bacteria. MADS interacts with a CRISPR-Cas system in its native host to provide robust and durable resistance against phages. While phages can acquire epigenetic-mediated resistance against MADS, co-existence of MADS and a CRISPR-Cas system limits escape emergence. MADS comprises eight genes with predicted nuclease, ATPase, kinase, and methyltransferase domains, most of which are essential for either self/non-self discrimination, DNA restriction, or both. The complex genetic architecture of MADS and MADS-like systems, relative to other prokaryotic defenses, points toward highly elaborate mechanisms of sensing infections, defense activation, and/or interference.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"44 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141862425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A human commensal-pathogenic fungus suppresses host immunity via targeting TBK1","authors":"","doi":"10.1016/j.chom.2024.07.003","DOIUrl":"https://doi.org/10.1016/j.chom.2024.07.003","url":null,"abstract":"<p><em>Candida albicans</em> stably colonizes humans but is the leading cause of hospital-acquired fungemia. Traditionally, masking immunogenic moieties has been viewed as a tactic for immune evasion. Here, we demonstrate that <em>C. albicans</em> blocks type I interferon (IFN-I) signaling via translocating an effector protein Cmi1 into host cells. Mechanistically, Cmi1 binds and inhibits TANK-binding kinase 1 (TBK1) to abrogate IFN-regulatory factor 3 (IRF3) phosphorylation, thereby suppressing the IFN-I cascade. Murine infection with a <em>cmi1</em> mutant displays an exaggerated IFN-I response in both kidneys and bone-marrow-derived macrophages, leading to rapid fungal clearance and host survival. Remarkably, the lack of <em>CMI1</em> compromises gut commensalism and increases IFN-I response in mouse colonic cells. These phenotypes of <em>cmi1</em> are rescued by the depletion of IFN-I receptor. This work establishes the importance of TBK1 inhibition in fungal pathogenesis and reveals that a human commensal-pathogenic fungus significantly impacts host immunity during gut colonization and infection via delivering effector proteins into host cells.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"68 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor","authors":"","doi":"10.1016/j.chom.2024.06.010","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.010","url":null,"abstract":"<p>The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic T cells and immune cytokines in blood and tumors. We isolated <em>Prevotella merdae</em> Immunoactis from a responder to FMT, which stimulates T cell activity and suppresses tumor growth in mice by enhancing cytotoxic T cell infiltration. Additionally, we found <em>Lactobacillus salivarius</em> and <em>Bacteroides plebeius</em> may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"22 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK","authors":"","doi":"10.1016/j.chom.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.chom.2024.07.001","url":null,"abstract":"<p><em>Peptostreptococcus stomatis</em> (<em>P. stomatis</em>) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that <em>P. stomatis</em> accelerates colonic tumorigenesis in <em>Apc</em><sup>Min/+</sup> and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. <em>P. stomatis</em> adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of <em>P. stomatis</em>. <em>P. stomatis</em>-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. <em>P. stomatis</em> also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAF<sup>V600E</sup>-mutant CRC xenografts. Thus, we identify <em>P. stomatis</em> as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"29 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery","authors":"","doi":"10.1016/j.chom.2024.06.014","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.014","url":null,"abstract":"<p>Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (<em>bai</em>) operon and production of LCA both <em>in vitro</em> and <em>in vivo</em>. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"25 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin","authors":"","doi":"10.1016/j.chom.2024.06.015","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.015","url":null,"abstract":"<p>Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population and how this heterogeneity affects virus evolution. Here, we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of two H3N2 strains, A/Hong Kong/45/2019 and A/Perth/16/2009, affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that were fixed in influenza variants after 2020 cause greater escape from sera from younger individuals compared with adults. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups and suggest approaches to understand how this heterogeneous selection shapes viral evolution.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"48 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease","authors":"","doi":"10.1016/j.chom.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.013","url":null,"abstract":"<p>Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60<sup>Δ/ΔIEC</sup>). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60<sup>Δ/ΔIEC</sup>;AhR<sup>−/−</sup>) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60<sup>Δ/ΔIEC</sup>;Il10<sup>−/−</sup>), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60<sup>Δ/ΔIEC</sup> mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60<sup>Δ/ΔIEC</sup> mice with the synthetic community OMM<sup>12</sup> reveals expansion of metabolically flexible <em>Bacteroides</em>, and <em>B. caecimuris</em> mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (<em>Ido1</em>, <em>Nos2</em>, <em>Duox2</em>). These signatures are observed in samples from Crohn’s disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"63 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Obesity-enriched gut microbe degrades myo-inositol and promotes lipid absorption","authors":"Chao Wu, Fangming Yang, Huanzi Zhong, Jie Hong, Huibin Lin, Mingxi Zong, Huahui Ren, Shaoqian Zhao, Yufei Chen, Zhun Shi, Xingyu Wang, Juan Shen, Qiaoling Wang, Mengshan Ni, Banru Chen, Zhongle Cai, Minchun Zhang, Zhiwen Cao, Kui Wu, Aibo Gao, Ruixin Liu","doi":"10.1016/j.chom.2024.06.012","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.012","url":null,"abstract":"<p>Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a <em>Megamonas</em>-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of <em>Megamonas</em> and polygenic risk exhibited an additive impact on obesity. <em>Megamonas rupellensis</em> possessed genes for <em>myo</em>-inositol degradation, as demonstrated <em>in vitro</em> and <em>in vivo</em>, and the addition of <em>myo</em>-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with <em>M. rupellensis</em> or <em>E. coli</em> heterologously expressing the <em>myo</em>-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for <em>M. rupellensis</em> as a <em>myo</em>-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"1 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Combatting superbugs using the evolutionary record of microbial warfare","authors":"Arjun S. Raman","doi":"10.1016/j.chom.2024.06.001","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.001","url":null,"abstract":"<p>New therapies to treat multi-drug-resistant (MDR) pathogens are needed. Santos-Júnior et al. discover new antimicrobials by leveraging the history of warfare within microbial communities. This study in <em>Cell</em> highlights the immense power of combining large biological databases with emerging computational methods, creating a key resource (AMPSphere) to be used for treating superbugs.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"16 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Opening another door on influenza entry","authors":"Daniel H. Goldhill","doi":"10.1016/j.chom.2024.06.011","DOIUrl":"https://doi.org/10.1016/j.chom.2024.06.011","url":null,"abstract":"<p>In this issue of <em>Cell Host & Microbe</em>, Karakus et al. find that an influenza virus enters cells by exclusively binding to a protein instead of sugars.</p>","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":"29 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}