Matthias Huelsmann, Olga T. Schubert, Martin Ackermann
{"title":"A framework for understanding collective microbiome metabolism","authors":"Matthias Huelsmann, Olga T. Schubert, Martin Ackermann","doi":"10.1038/s41564-024-01850-3","DOIUrl":"10.1038/s41564-024-01850-3","url":null,"abstract":"Microbiome metabolism underlies numerous vital ecosystem functions. Individual microbiome members often perform partial catabolism of substrates or do not express all of the metabolic functions required for growth. Microbiome members can complement each other by exchanging metabolic intermediates and cellular building blocks to achieve a collective metabolism. We currently lack a mechanistic framework to explain why microbiome members adopt partial metabolism and how metabolic functions are distributed among them. Here we argue that natural selection for proteome efficiency—that is, performing essential metabolic fluxes at a minimal protein investment—explains partial metabolism of microbiome members, which underpins the collective metabolism of microbiomes. Using the carbon cycle as an example, we discuss motifs of collective metabolism, the conditions under which these motifs increase the proteome efficiency of individuals and the metabolic interactions they result in. In summary, we propose a mechanistic framework for how collective metabolic functions emerge from selection on individuals. This Perspective explores why microbiome members perform partial metabolism of substrates and suggests that proteome efficiency is a driver of collective microbiome metabolism.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3097-3109"},"PeriodicalIF":20.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712443","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}
Lukas Hafner, Enzo Gadin, Lei Huang, Arthur Frouin, Fabien Laporte, Charlotte Gaultier, Afonso Vieira, Claire Maudet, Hugo Varet, Alexandra Moura, Hélène Bracq-Dieye, Nathalie Tessaud-Rita, Mylène Maury, Melody Dazas, Rachel Legendre, Pauline Gastineau, Yu-Huan Tsai, Jean-Yves Coppée, Caroline Charlier, Etienne Patin, Rayan Chikhi, Eduardo P. C. Rocha, Alexandre Leclercq, Olivier Disson, Hugues Aschard, Marc Lecuit
{"title":"Differential stress responsiveness determines intraspecies virulence heterogeneity and host adaptation in Listeria monocytogenes","authors":"Lukas Hafner, Enzo Gadin, Lei Huang, Arthur Frouin, Fabien Laporte, Charlotte Gaultier, Afonso Vieira, Claire Maudet, Hugo Varet, Alexandra Moura, Hélène Bracq-Dieye, Nathalie Tessaud-Rita, Mylène Maury, Melody Dazas, Rachel Legendre, Pauline Gastineau, Yu-Huan Tsai, Jean-Yves Coppée, Caroline Charlier, Etienne Patin, Rayan Chikhi, Eduardo P. C. Rocha, Alexandre Leclercq, Olivier Disson, Hugues Aschard, Marc Lecuit","doi":"10.1038/s41564-024-01859-8","DOIUrl":"10.1038/s41564-024-01859-8","url":null,"abstract":"Microbial pathogenesis is mediated by the expression of virulence genes. However, as microbes with identical virulence gene content can differ in their pathogenic potential, other virulence determinants must be involved. Here, by combining comparative genomics and transcriptomics of a large collection of isolates of the model pathogen Listeria monocytogenes, time-lapse microscopy, in vitro evolution and in vivo experiments, we show that the individual stress responsiveness of L. monocytogenes isolates determines their respective levels of virulence in vivo and reflects their degree of host adaptation. The transcriptional signature that accounts for the heterogeneity in the virulence of L. monocytogenes species is mediated by the stress response regulator SigB and driven by differential stress responsiveness. The tuning of SigB pathway responsiveness is polygenic and influenced by multiple, individually rare gene variations. This study reveals an overarching determinant of microbial virulence, challenging the paradigm of accessory virulence gene content as the major determinant of intraspecies virulence heterogeneity. Differences in virulence across the Listeria monocytogenes species are determined by the fine-tuning of SigB pathway responsiveness and reflect host adaptation.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3345-3361"},"PeriodicalIF":20.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684161","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}
{"title":"Parkinson’s drug starves gut microbes of iron","authors":"Jan Homolak, Lara Berg, Lisa Maier","doi":"10.1038/s41564-024-01863-y","DOIUrl":"10.1038/s41564-024-01863-y","url":null,"abstract":"Entacapone, a drug used in the treatment of Parkinson’s disease, disrupts gut microbial communities by sequestering iron, creating a competitive advantage for iron-scavenging microbes that often carry antimicrobial resistance and virulence genes.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3090-3092"},"PeriodicalIF":20.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684160","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}
Harshad Ingle, Jerome M. Molleston, Paige D. Hall, Duyen Bui, Leran Wang, Karan D. Bhatt, Lynne Foster, Avan Antia, Siyuan Ding, Sanghyun Lee, Daved H. Fremont, Megan T. Baldridge
{"title":"The neonatal Fc receptor is a cellular receptor for human astrovirus","authors":"Harshad Ingle, Jerome M. Molleston, Paige D. Hall, Duyen Bui, Leran Wang, Karan D. Bhatt, Lynne Foster, Avan Antia, Siyuan Ding, Sanghyun Lee, Daved H. Fremont, Megan T. Baldridge","doi":"10.1038/s41564-024-01855-y","DOIUrl":"10.1038/s41564-024-01855-y","url":null,"abstract":"Human astroviruses (HAstV) are major causes of gastroenteritis, especially in children, and there are no vaccines or antivirals currently available. Little is known about host factors required for their cellular entry. Here we utilized complementary CRISPR-Cas9-based knockout and activation screens to identify neonatal Fc receptor (FcRn) and dipeptidyl-peptidase IV (DPP4) as entry factors for HAstV infection in vitro. Disruption of FcRn or DPP4 reduced HAstV infection in permissive cells and, reciprocally, overexpression of these factors in non-permissive cells was sufficient to promote infection. We observed direct binding of FcRn, but not DPP4, with HAstV virions and the purified spike protein. This suggests that FcRn is a receptor for HAstVs while DPP4 is a cofactor for entry. Inhibitors for DPP4 and FcRn currently in clinical use prevented HAstV infection in cell lines and human enteroids. Our results reveal mechanisms of HAstV entry as well as druggable targets to limit HAstV infection. A CRISPR-based screen identifies neonatal Fc receptor (FcRn) and dipeptidyl-peptidase IV (DPP4) as entry factors for human astrovirus, and targeting them using available therapies effectively prevents infection in human enteroid cultures.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3321-3331"},"PeriodicalIF":20.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684162","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}
Fátima C. Pereira, Xiaowei Ge, Jannie M. Kristensen, Rasmus H. Kirkegaard, Klara Maritsch, Dávid Szamosvári, Stefanie Imminger, David Seki, Juwairiyah B. Shazzad, Yifan Zhu, Marie Decorte, Bela Hausmann, David Berry, Kenneth Wasmund, Arno Schintlmeister, Thomas Böttcher, Ji-Xin Cheng, Michael Wagner
{"title":"The Parkinson’s disease drug entacapone disrupts gut microbiome homeostasis via iron sequestration","authors":"Fátima C. Pereira, Xiaowei Ge, Jannie M. Kristensen, Rasmus H. Kirkegaard, Klara Maritsch, Dávid Szamosvári, Stefanie Imminger, David Seki, Juwairiyah B. Shazzad, Yifan Zhu, Marie Decorte, Bela Hausmann, David Berry, Kenneth Wasmund, Arno Schintlmeister, Thomas Böttcher, Ji-Xin Cheng, Michael Wagner","doi":"10.1038/s41564-024-01853-0","DOIUrl":"10.1038/s41564-024-01853-0","url":null,"abstract":"Many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, the mechanisms underlying these effects are not well known. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single-cell chemical imaging to investigate the impact of two widely prescribed drugs on the gut microbiome. Physiologically relevant concentrations of entacapone, a treatment for Parkinson’s disease, or loxapine succinate, used to treat schizophrenia, were incubated ex vivo with human faecal samples. Both drugs significantly impact microbial activity, more so than microbial abundance. Mechanistically, entacapone can complex and deplete available iron resulting in gut microbiome composition and function changes. Microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Further, entacapone-induced iron starvation selected for iron-scavenging gut microbiome members encoding antimicrobial resistance and virulence genes. These findings reveal the impact of two under-investigated drugs on whole microbiomes and identify metal sequestration as a mechanism of drug-induced microbiome disturbance. Entacapone, a Parkinson’s disease medication, sequesters iron resulting in a selective inhibition of gut microbial activity.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3165-3183"},"PeriodicalIF":20.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01853-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678277","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}
{"title":"Engineering history with Asgard archaea of the kingdom Promethearchaeati","authors":"Masaru K. Nobu","doi":"10.1038/s41564-024-01866-9","DOIUrl":"10.1038/s41564-024-01866-9","url":null,"abstract":"Multiple histories converge in Masaru Nobu’s story of culturing an archaeon closely related to us eukaryotes.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3086-3087"},"PeriodicalIF":20.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673236","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}
{"title":"Coffee habits help shape gut communities","authors":"Nathan P. McNulty, Jeffrey I. Gordon","doi":"10.1038/s41564-024-01869-6","DOIUrl":"10.1038/s41564-024-01869-6","url":null,"abstract":"Routine coffee consumption is associated with a gut microbiome signature characterized by elevated levels of Lawsonibacter asaccharolyticus. The growth of this bacterium is stimulated by coffee in vitro and its activities may influence the biotransformation of coffee-associated metabolites.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3088-3089"},"PeriodicalIF":20.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673227","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}
Mark J. G. Bakkers, Freek Cox, Annemart Koornneef, Xiaodi Yu, Daan van Overveld, Lam Le, Ward van den Hoogen, Joost Vaneman, Anne Thoma, Richard Voorzaat, Lisanne Tettero, Jarek Juraszek, Leslie van der Fits, Roland Zahn, Johannes P. M. Langedijk
{"title":"A foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses","authors":"Mark J. G. Bakkers, Freek Cox, Annemart Koornneef, Xiaodi Yu, Daan van Overveld, Lam Le, Ward van den Hoogen, Joost Vaneman, Anne Thoma, Richard Voorzaat, Lisanne Tettero, Jarek Juraszek, Leslie van der Fits, Roland Zahn, Johannes P. M. Langedijk","doi":"10.1038/s41564-024-01860-1","DOIUrl":"10.1038/s41564-024-01860-1","url":null,"abstract":"Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the prefusion conformation and linked to a heterologous foldon trimerization domain to obtain a prefusion F (preF) trimer. Here we show that current RSV vaccines induce undesirable anti-foldon antibodies in non-human primates, mice and humans. To overcome this, we designed a foldon-free RSV preF trimer by elucidating the structural basis of trimerization-induced preF destabilization through molecular dynamics simulations and by introducing amino acid substitutions that negate hotspots of charge repulsion. The highly stable prefusion conformation was validated using antigenic and cryo-electron microscopy analysis. The preF is immunogenic and protective in naive mouse models and boosts neutralizing antibody titres in RSV-pre-exposed mice and non-human primates, while achieving similar titres to approved RSV vaccines in mice. This stable preF design is a promising option as a foldon-independent candidate for a next-generation RSV vaccine immunogen. A targeted design to stabilize the respiratory syncytial virus prefusion F trimer enables the generation of a foldon-free immunogen that elicits similar humoral responses to approved vaccines.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3254-3267"},"PeriodicalIF":20.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01860-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673234","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}
Hans Carolus, Dimitrios Sofras, Giorgio Boccarella, Poppy Sephton-Clark, Vladislav Biriukov, Nicholas C. Cauldron, Celia Lobo Romero, Rudy Vergauwen, Saleh Yazdani, Siebe Pierson, Stef Jacobs, Paul Vandecruys, Stefanie Wijnants, Jacques F. Meis, Toni Gabaldón, Pieter van den Berg, Jeffrey M. Rybak, Christina A. Cuomo, Patrick Van Dijck
{"title":"Acquired amphotericin B resistance leads to fitness trade-offs that can be mitigated by compensatory evolution in Candida auris","authors":"Hans Carolus, Dimitrios Sofras, Giorgio Boccarella, Poppy Sephton-Clark, Vladislav Biriukov, Nicholas C. Cauldron, Celia Lobo Romero, Rudy Vergauwen, Saleh Yazdani, Siebe Pierson, Stef Jacobs, Paul Vandecruys, Stefanie Wijnants, Jacques F. Meis, Toni Gabaldón, Pieter van den Berg, Jeffrey M. Rybak, Christina A. Cuomo, Patrick Van Dijck","doi":"10.1038/s41564-024-01854-z","DOIUrl":"10.1038/s41564-024-01854-z","url":null,"abstract":"Candida auris is a growing concern due to its resistance to antifungal drugs, particularly amphotericin B (AMB), detected in 30 to 60% of clinical isolates. However, the mechanisms of AMB resistance remain poorly understood. Here we investigated 441 in vitro- and in vivo-evolved C. auris lineages from 4 AMB-susceptible clinical strains of different clades. Genetic and sterol analyses revealed four major types of sterol alterations as a result of clinically rare variations in sterol biosynthesis genes ERG6, NCP1, ERG11, ERG3, HMG1, ERG10 and ERG12. In addition, aneuploidies in chromosomes 4 and 6 emerged during resistance evolution. Fitness trade-off phenotyping and mathematical modelling identified diverse strain- and mechanism-dependent fitness trade-offs. Variation in CDC25 rescued fitness trade-offs, thereby increasing the infection capacity. This possibly contributed to therapy-induced acquired AMB resistance in the clinic. Our findings highlight sterol-modulating mechanisms and fitness trade-off compensation as risks for AMB treatment failure in clinical settings. The fungal pathogen Candida auris can acquire amphotericin B resistance through clinically rare mutations in sterol biosynthesis genes but at a certain fitness cost, which reduces its infection potential. Compensatory evolution can, however, mitigate this cost.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"9 12","pages":"3304-3320"},"PeriodicalIF":20.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673261","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}
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