Pub Date : 2025-12-15DOI: 10.1038/s41564-025-02242-x
Alaina R. Weinheimer, Julia M. Brown, Brian Thompson, Greta Leonaviciene, Vaidotas Kiseliovas, Simonas Jocys, Jacob Munson-McGee, Gregory Gavelis, Corianna Mascena, Linas Mazutis, Nicole J. Poulton, Rapolas Zilionis, Ramunas Stepanauskas
{"title":"Author Correction: Single-particle genomics uncovers abundant non-canonical marine viruses from nanolitre volumes","authors":"Alaina R. Weinheimer, Julia M. Brown, Brian Thompson, Greta Leonaviciene, Vaidotas Kiseliovas, Simonas Jocys, Jacob Munson-McGee, Gregory Gavelis, Corianna Mascena, Linas Mazutis, Nicole J. Poulton, Rapolas Zilionis, Ramunas Stepanauskas","doi":"10.1038/s41564-025-02242-x","DOIUrl":"10.1038/s41564-025-02242-x","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"337-337"},"PeriodicalIF":19.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02242-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proliferation of the emerging zoonotic pathogen Streptococcus equi subsp. zooepidemicus in the meninges is linked to mortality in pigs and morbidity in humans. The mechanisms underlying the remarkable capacity of hypervirulent S. zooepidemicus to proliferate in cerebrospinal fluid (CSF) are largely undefined. Here, using genetically barcoded S. zooepidemicus, we found that following systemic infection of mice, only ~1–10 S. zooepidemicus clones invade the meninges where they subsequently replicate ~107-fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTSman)-defective strains, identified the PTSman, which imports glucose, as essential for S. zooepidemicus proliferation in CSF. The S. zooepidemicus PTSman promoter confers species-specific constitutive transcription of PTSman, enabling glucose acquisition at low glucose concentrations and limiting activation of the stringent response, leading to pathogen replication in CSF. Our findings reveal how the rewiring of PTSman in the control of S. zooepidemicus metabolism enables this pathogen to adapt to and replicate in CSF during meningitis. Streptococcus equi subsp. zooepidemicus imports glucose via the bacterial mannose phosphotransferase system (PTSman), which inhibits stringent response, supports growth in cerebrospinal fluid and promotes brain damage during meningitis.
{"title":"Zoonotic Streptococcus imports glucose to inhibit stringent response and promote growth during meningitis","authors":"Chen Yuan, Karthik Hullahalli, Hao Huang, Siqi Zhao, Wenqing Wang, Xingyu Tian, Xin Li, Linya Xia, Yuchang Wang, Fei Pan, Ying Liang, Yurui Xie, Yue Li, Hongjie Fan, Matthew K. Waldor, Zhe Ma","doi":"10.1038/s41564-025-02194-2","DOIUrl":"10.1038/s41564-025-02194-2","url":null,"abstract":"Proliferation of the emerging zoonotic pathogen Streptococcus equi subsp. zooepidemicus in the meninges is linked to mortality in pigs and morbidity in humans. The mechanisms underlying the remarkable capacity of hypervirulent S. zooepidemicus to proliferate in cerebrospinal fluid (CSF) are largely undefined. Here, using genetically barcoded S. zooepidemicus, we found that following systemic infection of mice, only ~1–10 S. zooepidemicus clones invade the meninges where they subsequently replicate ~107-fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTSman)-defective strains, identified the PTSman, which imports glucose, as essential for S. zooepidemicus proliferation in CSF. The S. zooepidemicus PTSman promoter confers species-specific constitutive transcription of PTSman, enabling glucose acquisition at low glucose concentrations and limiting activation of the stringent response, leading to pathogen replication in CSF. Our findings reveal how the rewiring of PTSman in the control of S. zooepidemicus metabolism enables this pathogen to adapt to and replicate in CSF during meningitis. Streptococcus equi subsp. zooepidemicus imports glucose via the bacterial mannose phosphotransferase system (PTSman), which inhibits stringent response, supports growth in cerebrospinal fluid and promotes brain damage during meningitis.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"125-141"},"PeriodicalIF":19.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02194-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The innate immune response involves interferons (IFNs), antiviral cytokines that upregulate numerous IFN-stimulated genes, many of which have uncharacterized functions and mechanisms. Here we performed transcriptomic profiling of lung tissues from wild-type and IFNAR−/− mice infected with SARS-CoV-2 and single-cell RNA sequencing of bronchoalveolar lavage fluid and peripheral blood mononuclear cells from patients with COVID-19. We identified O-GalNAc transferase 2 (GALNT2), an N-acetylgalactosaminyltransferase, as an antiviral IFN-stimulated gene restricting the replication of multiple coronaviruses and influenza A viruses in vitro and in vivo, contributing to viral clearance and reducing disease severity. Mechanistically, GALNT2-dependent O-linked glycosylation may regulate viral glycoprotein proteolytic processing and impair viral growth by blocking virus–cell fusion. In addition, we found that serine residues at 810/813 in the viral spike protein undergo O-glycosylation and function as the primary genetic determinants of sensitivity or evasion towards GALNT2. Human genetic data analysis revealed that individuals with GALNT2 variants that lost antiviral function had elevated risk of hospitalization following SARS-CoV-2 infection. This study establishes GALNT2 as an antiviral factor against some respiratory virus infections. The authors find that O-GalNAc transferase 2 (GALNT2) restricts viral infection, probably through the regulation of the proteolytic processing of viral glycoproteins via its O-linked glycosylation activity, impairing virus–cell fusion.
{"title":"Interferon-stimulated gene GALNT2 restricts respiratory virus infections","authors":"Wei Ran, Jinghong Yang, Shi Yu, Qingtao Hu, Yuqi He, Shengjun Wang, Cheng Wei, Jing Sun, Airu Zhu, Fang Li, Lu Zhang, Pengfei Li, Huina Hu, Ruangang Pan, Yanying Yu, Yanqiu Yuan, Lingyu Sun, Yanqun Wang, Zhaoyong Zhang, Zhao Chen, Donglan Liu, Qihong Yan, Dong Wang, Kuai Yu, Yiliang Wang, Jianfen Zhuo, Zhen Zhuang, Hua Tao, Qiuhui Zeng, Kaixin Zhou, Fenghua Chen, Wenxuan Tang, Yuzheng Zhou, Rong Bai, Yonghao Xu, Na Li, Jun Dai, Hongyu Zhao, Jung-Eun Park, Tao Wang, Qiang Ding, Stanley Perlman, Jingxian Zhao, Yang Mao, Shaobo Wang, Jincun Zhao","doi":"10.1038/s41564-025-02200-7","DOIUrl":"10.1038/s41564-025-02200-7","url":null,"abstract":"The innate immune response involves interferons (IFNs), antiviral cytokines that upregulate numerous IFN-stimulated genes, many of which have uncharacterized functions and mechanisms. Here we performed transcriptomic profiling of lung tissues from wild-type and IFNAR−/− mice infected with SARS-CoV-2 and single-cell RNA sequencing of bronchoalveolar lavage fluid and peripheral blood mononuclear cells from patients with COVID-19. We identified O-GalNAc transferase 2 (GALNT2), an N-acetylgalactosaminyltransferase, as an antiviral IFN-stimulated gene restricting the replication of multiple coronaviruses and influenza A viruses in vitro and in vivo, contributing to viral clearance and reducing disease severity. Mechanistically, GALNT2-dependent O-linked glycosylation may regulate viral glycoprotein proteolytic processing and impair viral growth by blocking virus–cell fusion. In addition, we found that serine residues at 810/813 in the viral spike protein undergo O-glycosylation and function as the primary genetic determinants of sensitivity or evasion towards GALNT2. Human genetic data analysis revealed that individuals with GALNT2 variants that lost antiviral function had elevated risk of hospitalization following SARS-CoV-2 infection. This study establishes GALNT2 as an antiviral factor against some respiratory virus infections. The authors find that O-GalNAc transferase 2 (GALNT2) restricts viral infection, probably through the regulation of the proteolytic processing of viral glycoproteins via its O-linked glycosylation activity, impairing virus–cell fusion.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"256-270"},"PeriodicalIF":19.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02200-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1038/s41564-025-02198-y
Ricardo Fróis-Martins, Kontxi Martinez de San Vicente, Corinne Maufrais, Sarah Mertens, Natacha Sertour, Emilie Sitterlé, Marie-Elisabeth Bougnoux, Christophe d’Enfert, Salomé LeibundGut-Landmann
Candida albicans is a common resident of the microbiota that supports host homeostasis but can cause disease when immune defences are impaired. Mucocutaneous candidiasis in individuals with IL-17 immune defects provides insights into the immune system’s role in controlling C. albicans. Here, using a murine model of oral colonization, we show that IL-17 signalling maintains C. albicans in a non-pathogenic state. Loss of IL-17 leads to fungal filamentation and upregulation of hyphae-associated genes, which is accompanied by epithelial barrier disruption and inflammation, linked to aberrant IL-22 and IL-13 production. The emergence of pathogenic fungal traits was associated with impaired zinc chelation due to reduced calprotectin expression in the IL-17-deficient mice. Prolonged exposure to the immune-dysregulated tissue led to selection of stable, damage-inducing C. albicans variants, mirroring the evolution of isolates from a chronic mucocutaneous candidiasis patient. These findings reveal how IL-17 protects against fungal pathogenicity and how immune dysfunction fosters C. albicans adaptation and diversification within the host. IL-17 signalling restricts C. albicans pathogenicity in the colonized oral cavity. Lack of IL-17 is associated with overt filamentation due to impaired zinc nutritional immunity and over time leads to the evolution of pathogenic strain variants.
{"title":"IL-17-mediated antifungal immunity restricts Candida albicans pathogenicity in the oral cavity","authors":"Ricardo Fróis-Martins, Kontxi Martinez de San Vicente, Corinne Maufrais, Sarah Mertens, Natacha Sertour, Emilie Sitterlé, Marie-Elisabeth Bougnoux, Christophe d’Enfert, Salomé LeibundGut-Landmann","doi":"10.1038/s41564-025-02198-y","DOIUrl":"10.1038/s41564-025-02198-y","url":null,"abstract":"Candida albicans is a common resident of the microbiota that supports host homeostasis but can cause disease when immune defences are impaired. Mucocutaneous candidiasis in individuals with IL-17 immune defects provides insights into the immune system’s role in controlling C. albicans. Here, using a murine model of oral colonization, we show that IL-17 signalling maintains C. albicans in a non-pathogenic state. Loss of IL-17 leads to fungal filamentation and upregulation of hyphae-associated genes, which is accompanied by epithelial barrier disruption and inflammation, linked to aberrant IL-22 and IL-13 production. The emergence of pathogenic fungal traits was associated with impaired zinc chelation due to reduced calprotectin expression in the IL-17-deficient mice. Prolonged exposure to the immune-dysregulated tissue led to selection of stable, damage-inducing C. albicans variants, mirroring the evolution of isolates from a chronic mucocutaneous candidiasis patient. These findings reveal how IL-17 protects against fungal pathogenicity and how immune dysfunction fosters C. albicans adaptation and diversification within the host. IL-17 signalling restricts C. albicans pathogenicity in the colonized oral cavity. Lack of IL-17 is associated with overt filamentation due to impaired zinc nutritional immunity and over time leads to the evolution of pathogenic strain variants.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"111-124"},"PeriodicalIF":19.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1038/s41564-025-02199-x
James C. Kosmopoulos, William Pallier, Ashish A. Malik, Karthik Anantharaman
Peatlands hold up to one-third of Earth’s soil carbon but are increasingly turning from being carbon sinks to becoming carbon sources due to human impacts. Restoration efforts aim to reverse this trend, but viral influences on peatland recovery remain unclear, despite viruses being potent regulators of microbiomes and ecosystem function. Here we sequenced soil metagenomes to study viral communities across seven UK peatlands, each encompassing areas representing three peatland ecosystem health statuses: natural, damaged and restored. We found that viral diversity and community structure were shaped by both geography and ecosystem health. Viruses were geographically widespread, yet exhibited ecosystem health-specific endemism and functional adaptation, highlighting their sensitivity to restoration. Virus–host dynamics ranged from stable ‘piggyback-the-winner’ relationships to decoupled dynamics in those infecting keystone aerobes, sulfate reducers, carbohydrate degraders and fermenters. These findings position viruses as dynamic drivers of peatland ecosystem recovery and could unlock pathways to bolster carbon retention and accelerate climate mitigation. Metagenomics shows that viral diversity and community structure are shaped by geography and ecosystem health status, positioning viruses as unexpected players in peatland restoration.
{"title":"Ecosystem health shapes viral ecology in peatland soils","authors":"James C. Kosmopoulos, William Pallier, Ashish A. Malik, Karthik Anantharaman","doi":"10.1038/s41564-025-02199-x","DOIUrl":"10.1038/s41564-025-02199-x","url":null,"abstract":"Peatlands hold up to one-third of Earth’s soil carbon but are increasingly turning from being carbon sinks to becoming carbon sources due to human impacts. Restoration efforts aim to reverse this trend, but viral influences on peatland recovery remain unclear, despite viruses being potent regulators of microbiomes and ecosystem function. Here we sequenced soil metagenomes to study viral communities across seven UK peatlands, each encompassing areas representing three peatland ecosystem health statuses: natural, damaged and restored. We found that viral diversity and community structure were shaped by both geography and ecosystem health. Viruses were geographically widespread, yet exhibited ecosystem health-specific endemism and functional adaptation, highlighting their sensitivity to restoration. Virus–host dynamics ranged from stable ‘piggyback-the-winner’ relationships to decoupled dynamics in those infecting keystone aerobes, sulfate reducers, carbohydrate degraders and fermenters. These findings position viruses as dynamic drivers of peatland ecosystem recovery and could unlock pathways to bolster carbon retention and accelerate climate mitigation. Metagenomics shows that viral diversity and community structure are shaped by geography and ecosystem health status, positioning viruses as unexpected players in peatland restoration.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"142-154"},"PeriodicalIF":19.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02199-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1038/s41564-025-02205-2
Antonio Serrano, Charles Puerner, Louis Chevalier, Emily Plumb, Johannes Elferich, Stephen Diggs, Ludwig Roman Sinn, Nikolaus Grigorieff, Markus Ralser, Morgan Delarue, Martine Bassilana, Robert Alan Arkowitz
The human fungal pathogen Candida albicans undergoes a morphological transition from a budding yeast to a filamentous form, which is associated with pathogenesis. Various cues mediate this transition including intracellular reorganization. The cytoplasm is densely packed with proteins including large macromolecular complexes, such as ribosomes, and hence, molecular crowding can impact a range of cellular processes. However, the relationship between cytoplasmic molecular crowding and morphological growth states is unclear. Using a fluorescent microrheological probe and single particle tracking, we observed a striking decrease in molecular crowding during filamentous growth in C. albicans. On the basis of simulations, proteomics and structural data from in situ cryogenic electron microscopy, we show that the reduction in crowding is due to a decrease in ribosome concentration that results in part from an inhibition of ribosome biogenesis, combined with an increase in cytoplasmic volume, leading to a dilution of ribosomes. Filamentation was enhanced in a mutant defective in ribosome biogenesis, while translation was not affected, suggesting that inhibition of ribosome biogenesis is a trigger for C. albicans morphogenesis. Overall, we show that filamentous growth is associated with reduced cytoplasmic crowding via changes in ribosome concentration, suggesting that combination therapies in which ribosome biogenesis is also targeted may be advantageous. During filamentous growth in the human fungal pathogen Candida albicans, a reduction in ribosome concentration leads to a decrease in macromolecular crowding. Inhibition of ribosome biogenesis can trigger filamentous growth in this pathogen.
{"title":"Decreased cytoplasmic crowding via inhibition of ribosome biogenesis can trigger Candida albicans filamentous growth","authors":"Antonio Serrano, Charles Puerner, Louis Chevalier, Emily Plumb, Johannes Elferich, Stephen Diggs, Ludwig Roman Sinn, Nikolaus Grigorieff, Markus Ralser, Morgan Delarue, Martine Bassilana, Robert Alan Arkowitz","doi":"10.1038/s41564-025-02205-2","DOIUrl":"10.1038/s41564-025-02205-2","url":null,"abstract":"The human fungal pathogen Candida albicans undergoes a morphological transition from a budding yeast to a filamentous form, which is associated with pathogenesis. Various cues mediate this transition including intracellular reorganization. The cytoplasm is densely packed with proteins including large macromolecular complexes, such as ribosomes, and hence, molecular crowding can impact a range of cellular processes. However, the relationship between cytoplasmic molecular crowding and morphological growth states is unclear. Using a fluorescent microrheological probe and single particle tracking, we observed a striking decrease in molecular crowding during filamentous growth in C. albicans. On the basis of simulations, proteomics and structural data from in situ cryogenic electron microscopy, we show that the reduction in crowding is due to a decrease in ribosome concentration that results in part from an inhibition of ribosome biogenesis, combined with an increase in cytoplasmic volume, leading to a dilution of ribosomes. Filamentation was enhanced in a mutant defective in ribosome biogenesis, while translation was not affected, suggesting that inhibition of ribosome biogenesis is a trigger for C. albicans morphogenesis. Overall, we show that filamentous growth is associated with reduced cytoplasmic crowding via changes in ribosome concentration, suggesting that combination therapies in which ribosome biogenesis is also targeted may be advantageous. During filamentous growth in the human fungal pathogen Candida albicans, a reduction in ribosome concentration leads to a decrease in macromolecular crowding. Inhibition of ribosome biogenesis can trigger filamentous growth in this pathogen.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"169-179"},"PeriodicalIF":19.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41564-025-02215-0
Primrose J. Boynton, Matthew R. Wengler
{"title":"Injecting bacteria into fungal hosts establishes stable endosymbiosis","authors":"Primrose J. Boynton, Matthew R. Wengler","doi":"10.1038/s41564-025-02215-0","DOIUrl":"10.1038/s41564-025-02215-0","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"11-11"},"PeriodicalIF":19.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41564-025-02177-3
Shaobo Yang, Zongqi Wang, Chengyuan Fang, Mengdi Yang, Saleh Khawaled, Shanna Bonanno, Neel S. Joshi, Yun Wei, Ke Zhang, Valeria Márquez-Pellegrin, Ming Guan, Songqi Zhang, Anna Clara Bader, Ningyuan Ye, Amber E. Haley, Michael K. Dame, Jason R. Spence, Xuesong He, James G. Fox, Ömer H. Yilmaz, Yatrik M. Shah, Rizwan Romee, Jiahe Li
Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (pks) island, is associated with host genotoxicity and tumorigenesis. However, no Food and Drug Administration-approved therapeutics directly target colibactin. Here we show that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shields the host from genotoxic effects across multiple pks+ isolates. The surface display, due to the fusion of ClbS with outer membrane protein A (ClbS–OmpA) in Escherichia coli, effectively reduced colibactin-induced DNA damage and cell cycle arrest in human cell lines and organoids, outperforming D-serine, a small-molecule inhibitor of colibactin synthesis. The engineered strains mitigated intestinal damage in a mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by pks+ E. coli. Our results show the feasibility of inhibiting bacterial genotoxins in the gut, establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites. Engineered Escherichia coli strains expressing a colibactin antitoxin, ClbS, on the surface prevent the genotoxic effects of colibactin released by genotoxin-producing bacteria in the mouse gut.
{"title":"Surface expression of antitoxin on engineered bacteria neutralizes genotoxic colibactin in the gut","authors":"Shaobo Yang, Zongqi Wang, Chengyuan Fang, Mengdi Yang, Saleh Khawaled, Shanna Bonanno, Neel S. Joshi, Yun Wei, Ke Zhang, Valeria Márquez-Pellegrin, Ming Guan, Songqi Zhang, Anna Clara Bader, Ningyuan Ye, Amber E. Haley, Michael K. Dame, Jason R. Spence, Xuesong He, James G. Fox, Ömer H. Yilmaz, Yatrik M. Shah, Rizwan Romee, Jiahe Li","doi":"10.1038/s41564-025-02177-3","DOIUrl":"10.1038/s41564-025-02177-3","url":null,"abstract":"Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (pks) island, is associated with host genotoxicity and tumorigenesis. However, no Food and Drug Administration-approved therapeutics directly target colibactin. Here we show that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shields the host from genotoxic effects across multiple pks+ isolates. The surface display, due to the fusion of ClbS with outer membrane protein A (ClbS–OmpA) in Escherichia coli, effectively reduced colibactin-induced DNA damage and cell cycle arrest in human cell lines and organoids, outperforming D-serine, a small-molecule inhibitor of colibactin synthesis. The engineered strains mitigated intestinal damage in a mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by pks+ E. coli. Our results show the feasibility of inhibiting bacterial genotoxins in the gut, establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites. Engineered Escherichia coli strains expressing a colibactin antitoxin, ClbS, on the surface prevent the genotoxic effects of colibactin released by genotoxin-producing bacteria in the mouse gut.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"53-66"},"PeriodicalIF":19.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type VI secretion systems (T6SSs) are molecular machines used by bacteria to release effectors that target either host cells, competing bacteria or fungi. Regulatory mechanisms underlying antifungal T6SS activity remain unexplored. Here we show, using mouse infection with wild-type and T6SS mutant bacteria, that T6SS activity of the enteropathogen, Yersinia pseudotuberculosis (Yptb), reduces fungal prevalence in the gut microbiota and has direct activity on Candida albicans. Screening of bacterial effector mutant strains, and structural and biochemical analyses identify TfeC as an antifungal chitinase T6SS effector that can kill C. albicans. In vivo experiments confirm that TfeC expression promotes Yptb colonization and reduces C. albicans abundance. We also show that Yptb senses the fungal quorum-sensing molecule, tyrosol, through the two-component system, EnvZ–OmpR, and responds by activating T6SS4. Our findings suggest that Yptb modulates its antifungal activities by detecting changes in fungal population density cues, revealing a mechanism of fungal–bacterial interkingdom communication mediated by fungal quorum-sensing molecules. Yersinia pseudotuberculosis senses fungal tyrosol signalling through EnvZ–OmpR which triggers T6SS activation and antifungal effector release to reduce fungal competitors in the mouse gut.
{"title":"Interkingdom sensing of fungal tyrosol promotes bacterial antifungal T6SS activity in the murine gut","authors":"Lingfang Zhu, Yuxin Zuo, Rui Cui, Peishuai Fu, Yuqi Liu, Zhuo Wang, Xinquan He, Danyang Yu, Zhiyan Wei, Shuyu Li, Yang Wang, Changfu Li, Yao Wang, De-Feng Li, Shuang-Jiang Liu, Xihui Shen","doi":"10.1038/s41564-025-02208-z","DOIUrl":"10.1038/s41564-025-02208-z","url":null,"abstract":"Type VI secretion systems (T6SSs) are molecular machines used by bacteria to release effectors that target either host cells, competing bacteria or fungi. Regulatory mechanisms underlying antifungal T6SS activity remain unexplored. Here we show, using mouse infection with wild-type and T6SS mutant bacteria, that T6SS activity of the enteropathogen, Yersinia pseudotuberculosis (Yptb), reduces fungal prevalence in the gut microbiota and has direct activity on Candida albicans. Screening of bacterial effector mutant strains, and structural and biochemical analyses identify TfeC as an antifungal chitinase T6SS effector that can kill C. albicans. In vivo experiments confirm that TfeC expression promotes Yptb colonization and reduces C. albicans abundance. We also show that Yptb senses the fungal quorum-sensing molecule, tyrosol, through the two-component system, EnvZ–OmpR, and responds by activating T6SS4. Our findings suggest that Yptb modulates its antifungal activities by detecting changes in fungal population density cues, revealing a mechanism of fungal–bacterial interkingdom communication mediated by fungal quorum-sensing molecules. Yersinia pseudotuberculosis senses fungal tyrosol signalling through EnvZ–OmpR which triggers T6SS activation and antifungal effector release to reduce fungal competitors in the mouse gut.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"240-255"},"PeriodicalIF":19.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-05DOI: 10.1038/s41564-025-02183-5
Oona Liedes, Arttu Reinholm, Nina Ekström, Anu Haveri, Anna Solastie, Saimi Vara, Willemijn F. Rijnink, Theo M. Bestebroer, Mathilde Richard, Rory D. de Vries, Pinja Jalkanen, Erika Lindh, Niina Ikonen, Alba Grifoni, Alessandro Sette, Terhi Laaksonen, Riikka Holopainen, Laura Kakkola, Maija Lappalainen, Ritva K. Syrjänen, Pekka Kolehmainen, Ilkka Julkunen, Hanna Nohynek, Merit Melin
Finland faced an outbreak of highly pathogenic clade 2.3.4.4b A(H5N1) avian influenza in 2023, which spread from wild birds to fur farms. Vaccinations of at-risk individuals began in June 2024 using the MF59-adjuvanted inactivated A(H5N8) vaccine (Seqirus; A/Astrakhan/3212/2020, clade 2.3.4.4b). Here, in an observational study, we assessed vaccine-induced immune responses in occupational at-risk individuals participating in the phase IV trial, including virus-specific antibody (n = 39 individuals) and T-cell (n = 18 individuals) responses. Vaccination elicited functional antibodies against the vaccine virus and two heterologous clade 2.3.4.4b strains associated with outbreaks on Finnish fur farms and dairy cattle in the United States. Among previously unvaccinated individuals, seroprotection rates against the vaccine virus were 83% (95% CI 70–97%) by microneutralization assay (titre ≥20) and 97% (90–100%) by haemagglutination inhibition assay (titre ≥40). In those previously vaccinated against avian influenza, a single dose induced seroprotection. A(H5N8)-specific memory CD4+ T-cell responses were detectable, with ~5-fold increase in IFNγ secretion after two doses. These results demonstrate that the vaccine probably provides cross-protection against circulating H5 clade 2.3.4.4b viruses. EU Clinical Trial Number 2023-509178-44-00. Vaccination of Finnish at-risk occupational groups with a clade 2.3.4.4b H5N8 influenza vaccine induced robust antibody and T-cell responses, supporting its potential to provide protection against current H5N1 outbreaks.
{"title":"Influenza A(H5N8) vaccine induces humoral and cell-mediated immunity against highly pathogenic avian influenza clade 2.3.4.4b A(H5N1) viruses in at-risk individuals","authors":"Oona Liedes, Arttu Reinholm, Nina Ekström, Anu Haveri, Anna Solastie, Saimi Vara, Willemijn F. Rijnink, Theo M. Bestebroer, Mathilde Richard, Rory D. de Vries, Pinja Jalkanen, Erika Lindh, Niina Ikonen, Alba Grifoni, Alessandro Sette, Terhi Laaksonen, Riikka Holopainen, Laura Kakkola, Maija Lappalainen, Ritva K. Syrjänen, Pekka Kolehmainen, Ilkka Julkunen, Hanna Nohynek, Merit Melin","doi":"10.1038/s41564-025-02183-5","DOIUrl":"10.1038/s41564-025-02183-5","url":null,"abstract":"Finland faced an outbreak of highly pathogenic clade 2.3.4.4b A(H5N1) avian influenza in 2023, which spread from wild birds to fur farms. Vaccinations of at-risk individuals began in June 2024 using the MF59-adjuvanted inactivated A(H5N8) vaccine (Seqirus; A/Astrakhan/3212/2020, clade 2.3.4.4b). Here, in an observational study, we assessed vaccine-induced immune responses in occupational at-risk individuals participating in the phase IV trial, including virus-specific antibody (n = 39 individuals) and T-cell (n = 18 individuals) responses. Vaccination elicited functional antibodies against the vaccine virus and two heterologous clade 2.3.4.4b strains associated with outbreaks on Finnish fur farms and dairy cattle in the United States. Among previously unvaccinated individuals, seroprotection rates against the vaccine virus were 83% (95% CI 70–97%) by microneutralization assay (titre ≥20) and 97% (90–100%) by haemagglutination inhibition assay (titre ≥40). In those previously vaccinated against avian influenza, a single dose induced seroprotection. A(H5N8)-specific memory CD4+ T-cell responses were detectable, with ~5-fold increase in IFNγ secretion after two doses. These results demonstrate that the vaccine probably provides cross-protection against circulating H5 clade 2.3.4.4b viruses. EU Clinical Trial Number 2023-509178-44-00. Vaccination of Finnish at-risk occupational groups with a clade 2.3.4.4b H5N8 influenza vaccine induced robust antibody and T-cell responses, supporting its potential to provide protection against current H5N1 outbreaks.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"155-168"},"PeriodicalIF":19.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02183-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：