Nature Microbiology最新文献

{"title":"Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models","authors":"Xin Wang, Hongwei Su, Joshua B. Wallach, Jeffrey C. Wagner, Benjamin J. Braunecker, Michelle Gardner, Kristine M. Guinn, Nicole C. Howard, Thais Klevorn, Kan Lin, Yue J. Liu, Yao Liu, Douaa Mugahid, Mark Rodgers, Jaimie Sixsmith, Shoko Wakabayashi, Junhao Zhu, Matthew Zimmerman, Véronique Dartois, JoAnne L. Flynn, Philana Ling Lin, Sabine Ehrt, Sarah M. Fortune, Eric J. Rubin, Dirk Schnappinger","doi":"10.1038/s41564-024-01913-5","DOIUrl":"10.1038/s41564-024-01913-5","url":null,"abstract":"Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain–NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag−/− mice. The TKS strain had an escape mutation rate of less than 10−10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model. Engineered kill-switch-encoding Mycobacterium tuberculosis infects, elicits immune responses and is cleared from immunocompetent and immunocompromised mice, providing a model of controlled tuberculosis infection.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"482-494"},"PeriodicalIF":20.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01913-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961332","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":"Vaccine-induced T cell responses control Orthoflavivirus challenge infection without neutralizing antibodies in humans","authors":"Shirin Kalimuddin, Christine Y. L. Tham, Yvonne F. Z. Chan, Shou Kit Hang, Kamini Kunasegaran, Adeline Chia, Candice Y. Y. Chan, Dorothy H. L. Ng, Jean X. Y. Sim, Hwee-Cheng Tan, Ayesa Syenina, An Qi Ngoh, Noor Zayanah Hamis, Valerie Chew, Yan Shan Leong, Jia Xin Yee, Jenny G. Low, Kuan Rong Chan, Eugenia Z. Ong, Antonio Bertoletti, Eng Eong Ooi","doi":"10.1038/s41564-024-01903-7","DOIUrl":"10.1038/s41564-024-01903-7","url":null,"abstract":"T cells have been identified as correlates of protection in viral infections. However, the level of vaccine-induced T cells needed and the extent to which they alone can control acute viral infection in humans remain uncertain. Here we conducted a double-blind, randomized controlled trial involving vaccination and challenge in 33 adult human volunteers, using the live–attenuated yellow fever (YF17D) and chimeric Japanese encephalitis–YF17D (JE/YF17D) vaccines. Both Orthoflavivirus vaccines share T cell epitopes but have different neutralizing antibody epitopes. The primary objective was to assess the extent to which vaccine-induced T cell responses, independent of neutralizing antibodies, were able to reduce post-challenge viral RNAaemia levels. Secondary objectives included an assessment of surrogate measures of viral control, including post-challenge antibody titres and symptomatic outcomes. YF17D vaccinees had reduced levels of JE/YF17D challenge viraemia, compared with those without previous YF17D vaccination (mean log10(area under the curve genome copies per ml): 2.23 versus 3.22; P = 0.039). Concomitantly, YF17D vaccinees had lower post-JE/YF17D challenge antibody titres that reduced JE virus plaque number by 50%, or PRNT50 (mean log10(PRNT50 titre): 1.87 versus 2.5; P < 0.0001) and symptomatic rates (6% (n = 1/16) versus 53% (n = 9/17), P = 0.007). There were no unexpected safety events. Importantly, after challenge infection, several vaccinees had undetectable viraemia and no seroconversion, even in the absence of neutralizing antibodies. Indeed, high vaccine-induced T cell responses, specifically against the capsid protein, were associated with a level of viral control conventionally interpreted as sterilizing immunity. Our findings reveal the importance of T cells in controlling acute viral infection and suggests a potential correlate of protection against orthoflaviviral infections. ClinicalTrials.gov registration: NCT05568953 . The authors demonstrate the effectiveness of T cells in controlling acute viral infections, without neutralizing antibodies, by conducting an Orthoflavivirus vaccination and challenge study in humans.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"374-387"},"PeriodicalIF":20.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01903-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961333","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":"A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity","authors":"Alexander A. Smith, Hongwei Su, Joshua Wallach, Yao Liu, Pauline Maiello, H. Jacob Borish, Caylin Winchell, Andrew W. Simonson, Philana Ling Lin, Mark Rodgers, Daniel Fillmore, Jennifer Sakal, Kan Lin, Valerie Vinette, Dirk Schnappinger, Sabine Ehrt, JoAnne L. Flynn","doi":"10.1038/s41564-024-01895-4","DOIUrl":"10.1038/s41564-024-01895-4","url":null,"abstract":"Improved vaccination strategies for tuberculosis are needed. Intravenous (i.v.) delivery of live attenuated Mycobacterium bovis BCG provides protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here we genetically engineered two strains, BCG-TetON-DL and BCG-TetOFF-DL, to either induce or inhibit expression of two phage lysin operons, respectively, upon tetracycline exposure. We show that lysin expression kills BCG in vitro, in infected macrophages, and following infection of immunocompetent (C57BL/6) and immunocompromised (SCID) mice. Modified BCG elicited similar immune responses and provided similar protection against Mtb challenge as wild-type BCG in mice. In macaques, cessation of tetracycline treatment reduced i.v.-administered BCG-TetOFF-DL numbers. Intravenous BCG-TetOFF-DL increased pulmonary CD4 T-cell responses compared with wild-type BCG-induced responses and provided robust protection against Mtb challenge. Sterilizing immunity occurred in 6 of 8 macaques compared with 2 of 8 wild-type BCG-immunized macaques. Thus, a ‘kill-switch’ BCG strain provides additional safety and robust protection against Mtb infection. Engineered Mycobacterium bovis BCG encoding tetracycline-controlled phage lysin kill switches elicits protective immunity against subsequent M. tuberculosis infection in mice and non-human primates.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"468-481"},"PeriodicalIF":20.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961334","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":"Use microbes to tackle food insecurity","authors":"","doi":"10.1038/s41564-024-01916-2","DOIUrl":"10.1038/s41564-024-01916-2","url":null,"abstract":"Global food insecurity is a growing crisis, but microbes could offer an effective tool for sustainable agriculture.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 1","pages":"1-1"},"PeriodicalIF":20.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01916-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939571","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":"Streptomyces secretes a siderophore that sensitizes competitor bacteria to phage infection","authors":"Zhiyu Zang, Chengqian Zhang, Kyoung Jin Park, Daniel A. Schwartz, Ram Podicheti, Jay T. Lennon, Joseph P. Gerdt","doi":"10.1038/s41564-024-01910-8","DOIUrl":"10.1038/s41564-024-01910-8","url":null,"abstract":"To overtake competitors, microbes produce and secrete secondary metabolites that kill neighbouring cells and sequester nutrients. This metabolite-mediated competition probably evolved in complex microbial communities in the presence of viral pathogens. We therefore hypothesized that microbes secrete natural products that make competitors sensitive to phage infection. We used a binary-interaction screen and chemical characterization to identify a secondary metabolite (coelichelin) produced by Streptomyces sp. that sensitizes its soil competitor Bacillus subtilis to phage infection in vitro. The siderophore coelichelin sensitized B. subtilis to a panel of lytic phages (SPO1, SP10, SP50, Goe2) via iron sequestration, which prevented the activation of B. subtilis Spo0A, the master regulator of the stationary phase and sporulation. Metabolomics analysis revealed that other bacterial natural products may also provide phage-mediated competitive advantages to their producers. Overall, this work reveals that synergy between natural products and phages can shape the outcomes of competition between microbes. A secondary metabolite sensitizes competitor Bacillus subtilis to a wide panel of lytic phages by sequestering iron and preventing the activation of Spo0A.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"362-373"},"PeriodicalIF":20.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935883","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":"A decade of advances in human gut microbiome-derived biotherapeutics","authors":"Alena. L. Pribyl, Philip Hugenholtz, Matthew A. Cooper","doi":"10.1038/s41564-024-01896-3","DOIUrl":"10.1038/s41564-024-01896-3","url":null,"abstract":"Microbiome science has evolved rapidly in the past decade, with high-profile publications suggesting that the gut microbiome is a causal determinant of human health. This has led to the emergence of microbiome-focused biotechnology companies and pharmaceutical company investment in the research and development of gut-derived therapeutics. Despite the early promise of this field, the first generation of microbiome-derived therapeutics (faecal microbiota products) have only recently been approved for clinical use. Next-generation therapies based on readily culturable and as-yet-unculturable colonic bacterial species (with the latter estimated to comprise 63% of all detected species) have not yet progressed to pivotal phase 3 trials. This reflects the many challenges involved in developing a new class of drugs in an evolving field. Here we discuss the evolution of the live biotherapeutics field over the past decade, from the development of first-generation products to the emergence of rationally designed second- and third-generation live biotherapeutics. Finally, we present our outlook for the future of this field. This Perspective reflects on advances made in the field of human gut microbiome-derived biotherapeutics, from faecal microbiota products to rationally designed second- and third-generation live biotherapeutics, and discusses the future of this developing field.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"301-312"},"PeriodicalIF":20.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935885","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":"Gut microbiome signatures of vegan, vegetarian and omnivore diets and associated health outcomes across 21,561 individuals","authors":"Gloria Fackelmann, Paolo Manghi, Niccolò Carlino, Vitor Heidrich, Gianmarco Piccinno, Liviana Ricci, Elisa Piperni, Alberto Arrè, Elco Bakker, Alice C. Creedon, Lucy Francis, Joan Capdevila Pujol, Richard Davies, Jonathan Wolf, Kate M. Bermingham, Sarah E. Berry, Tim D. Spector, Francesco Asnicar, Nicola Segata","doi":"10.1038/s41564-024-01870-z","DOIUrl":"10.1038/s41564-024-01870-z","url":null,"abstract":"As plant-based diets gain traction, interest in their impacts on the gut microbiome is growing. However, little is known about diet-pattern-specific metagenomic profiles across populations. Here we considered 21,561 individuals spanning 5 independent, multinational, human cohorts to map how differences in diet pattern (omnivore, vegetarian and vegan) are reflected in gut microbiomes. Microbial profiles distinguished these common diet patterns well (mean AUC = 0.85). Red meat was a strong driver of omnivore microbiomes, with corresponding signature microbes (for example, Ruminococcus torques, Bilophila wadsworthia and Alistipes putredinis) negatively correlated with host cardiometabolic health. Conversely, vegan signature microbes were correlated with favourable cardiometabolic markers and were enriched in omnivores consuming more plant-based foods. Diet-specific gut microbes partially overlapped with food microbiomes, especially with dairy microbes, for example, Streptococcus thermophilus, and typical soil microbes in vegans. The signatures of common western diet patterns can support future nutritional interventions and epidemiology. Using 21,561 individuals, the authors present a cross-sectional study of how gut microbiome signatures are associated with dietary intake patterns and with host health outcomes.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 1","pages":"41-52"},"PeriodicalIF":20.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01870-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934992","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":"Crucial stepping stones in freshwater microbiology","authors":"David A. Pearce, James E. Lawrence, Maria Luisa Avila Jimenez","doi":"10.1038/s41564-024-01898-1","DOIUrl":"10.1038/s41564-024-01898-1","url":null,"abstract":"Three different studies in this issue use metagenomics to study the bacterial and viral dynamics of freshwater microbiomes, highlighting the ecological and environmental drivers of these ecosystems.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 1","pages":"6-7"},"PeriodicalIF":20.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929423","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":"Oropouche virus and the urgent need for global surveillance","authors":"Marta Giovanetti","doi":"10.1038/s41564-024-01897-2","DOIUrl":"10.1038/s41564-024-01897-2","url":null,"abstract":"The Oropouche virus has long been overlooked, but following a recent global expansion the virologist Marta Giovanetti argues for a One Health strategy to address this emergent public health threat.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 1","pages":"2-3"},"PeriodicalIF":20.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929585","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":"Unravelling viral ecology and evolution over 20 years in a freshwater lake","authors":"Zhichao Zhou, Patricia Q. Tran, Cody Martin, Robin R. Rohwer, Brett J. Baker, Katherine D. McMahon, Karthik Anantharaman","doi":"10.1038/s41564-024-01876-7","DOIUrl":"10.1038/s41564-024-01876-7","url":null,"abstract":"As freshwater lakes undergo rapid anthropogenic change, long-term studies reveal key microbial dynamics, evolutionary shifts and biogeochemical interactions, yet the vital role of viruses remains overlooked. Here, leveraging a 20 year time series from Lake Mendota, WI, USA, we characterized 1.3 million viral genomes across time, seasonality and environmental factors. Double-stranded DNA phages from the class Caudoviricetes dominated the community. We identified 574 auxiliary metabolic gene families representing over 140,000 auxiliary metabolic genes, including important genes such as psbA (photosynthesis), pmoC (methane oxidation) and katG (hydrogen peroxide decomposition), which were consistently present and active across decades and seasons. Positive associations and niche differentiation between virus–host pairs, including keystone Cyanobacteria, methanotrophs and Nanopelagicales, emerged during seasonal changes. Inorganic carbon and ammonium influenced viral abundances, underscoring viral roles in both ‘top-down’ and ‘bottom-up’ interactions. Evolutionary processes favoured fitness genes, reduced genomic heterogeneity and dominant sub-populations. This study transforms understanding of viral ecology and evolution in Earth’s microbiomes. A long-term metagenomic time series reveals how viruses impact diversity, ecological dynamics and evolution of freshwater microbiomes.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 1","pages":"231-245"},"PeriodicalIF":20.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917052","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}