Pub Date : 2025-01-20DOI: 10.1038/s41564-024-01884-7
Xiaomin Yan, Yang Liu, Tingsong Hu, Zhenglanyi Huang, Chenxi Li, Lei Guo, Yuhang Liu, Nan Li, Hailin Zhang, Yue Sun, Le Yi, Jianmin Wu, Jiang Feng, Fuqiang Zhang, Tinglei Jiang, Changchun Tu, Biao He
Bats are natural hosts for many emerging viruses for which spillover to humans is a major risk, but the diversity and ecology of bat viruses is poorly understood. Here we generated 8,176 RNA viral metagenomes by metatranscriptomic sequencing of organ and swab samples from 4,143 bats representing 40 species across 52 locations in China. The resulting database, the BtCN-Virome, expands bat RNA virus diversity by over 3.4-fold. Some viruses in the BtCN-Virome are traced to mammals, birds, arthropods, mollusks and plants. Diet, infection dynamics and environmental parameters such as humidity and forest coverage shape virus distribution. Compared with those in the wild, bats dwelling in human settlements harboured more diverse viruses that also circulated in humans and domestic animals, including Nipah and Lloviu viruses not previously reported in China. The BtCN-Virome provides important insights into the genetic diversity, ecological drivers and circulation dynamics of bat viruses, highlighting the need for surveillance of bats near human settlements. Samples from over 4,000 bats representing 40 different species yield 8,176 viral metagenomes that expand RNA virus diversity and decipher environmental and anthropogenic factors influencing bat viral ecology.
{"title":"A compendium of 8,176 bat RNA viral metagenomes reveals ecological drivers and circulation dynamics","authors":"Xiaomin Yan, Yang Liu, Tingsong Hu, Zhenglanyi Huang, Chenxi Li, Lei Guo, Yuhang Liu, Nan Li, Hailin Zhang, Yue Sun, Le Yi, Jianmin Wu, Jiang Feng, Fuqiang Zhang, Tinglei Jiang, Changchun Tu, Biao He","doi":"10.1038/s41564-024-01884-7","DOIUrl":"10.1038/s41564-024-01884-7","url":null,"abstract":"Bats are natural hosts for many emerging viruses for which spillover to humans is a major risk, but the diversity and ecology of bat viruses is poorly understood. Here we generated 8,176 RNA viral metagenomes by metatranscriptomic sequencing of organ and swab samples from 4,143 bats representing 40 species across 52 locations in China. The resulting database, the BtCN-Virome, expands bat RNA virus diversity by over 3.4-fold. Some viruses in the BtCN-Virome are traced to mammals, birds, arthropods, mollusks and plants. Diet, infection dynamics and environmental parameters such as humidity and forest coverage shape virus distribution. Compared with those in the wild, bats dwelling in human settlements harboured more diverse viruses that also circulated in humans and domestic animals, including Nipah and Lloviu viruses not previously reported in China. The BtCN-Virome provides important insights into the genetic diversity, ecological drivers and circulation dynamics of bat viruses, highlighting the need for surveillance of bats near human settlements. Samples from over 4,000 bats representing 40 different species yield 8,176 viral metagenomes that expand RNA virus diversity and decipher environmental and anthropogenic factors influencing bat viral ecology.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"554-568"},"PeriodicalIF":20.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989987","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 : 2025-01-17DOI: 10.1038/s41564-024-01907-3
Beilun Wang, Peijun Lin, Yuwei Zhong, Xiao Tan, Yangyang Shen, Yi Huang, Kai Jin, Yan Zhang, Ying Zhan, Dian Shen, Meng Wang, Zhou Yu, Yihan Wu
Artificial intelligence (AI) is a promising approach to identify new antimicrobial compounds in diverse microbial species. Here we developed an AI-based, explainable deep learning model, EvoGradient, that predicts the potency of antimicrobial peptides (AMPs) and virtually modifies peptide sequences to produce more potent AMPs, akin to in silico directed evolution. We applied this model to peptides encoded in low-abundance human oral bacteria, resulting in the virtual evolution of 32 peptides into potent AMPs. Of these, the 6 most effective were synthesized and tested against multidrug-resistant pathogens and demonstrated activity against carbapenem-resistant species Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, and vancomycin-resistant Enterococcus faecium. The most potent AMP, pep-19-mod, was validated in vivo, achieving over 95% reduction in bacterial loads in mouse models of thigh infection through both systemic and local administration. Our approach advances the automatic identification and optimization of AMPs. An AI-based learning model is applied to low-abundance human oral bacteria and identifies antimicrobial peptides with efficacy against multidrug-resistant bacterial pathogens.
{"title":"Explainable deep learning and virtual evolution identifies antimicrobial peptides with activity against multidrug-resistant human pathogens","authors":"Beilun Wang, Peijun Lin, Yuwei Zhong, Xiao Tan, Yangyang Shen, Yi Huang, Kai Jin, Yan Zhang, Ying Zhan, Dian Shen, Meng Wang, Zhou Yu, Yihan Wu","doi":"10.1038/s41564-024-01907-3","DOIUrl":"10.1038/s41564-024-01907-3","url":null,"abstract":"Artificial intelligence (AI) is a promising approach to identify new antimicrobial compounds in diverse microbial species. Here we developed an AI-based, explainable deep learning model, EvoGradient, that predicts the potency of antimicrobial peptides (AMPs) and virtually modifies peptide sequences to produce more potent AMPs, akin to in silico directed evolution. We applied this model to peptides encoded in low-abundance human oral bacteria, resulting in the virtual evolution of 32 peptides into potent AMPs. Of these, the 6 most effective were synthesized and tested against multidrug-resistant pathogens and demonstrated activity against carbapenem-resistant species Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, and vancomycin-resistant Enterococcus faecium. The most potent AMP, pep-19-mod, was validated in vivo, achieving over 95% reduction in bacterial loads in mouse models of thigh infection through both systemic and local administration. Our approach advances the automatic identification and optimization of AMPs. An AI-based learning model is applied to low-abundance human oral bacteria and identifies antimicrobial peptides with efficacy against multidrug-resistant bacterial pathogens.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"332-347"},"PeriodicalIF":20.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987464","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 : 2025-01-17DOI: 10.1038/s41564-024-01909-1
Sathvik Palakurty, Michael S. Diamond
The hurdle for infection of human cells by many animal and insect viruses remains poorly understood. A study using a large-scale functional screening approach suggests that the entry step may be a lower barrier to zoonosis than previously anticipated.
{"title":"Viral entry as a low barrier to zoonosis","authors":"Sathvik Palakurty, Michael S. Diamond","doi":"10.1038/s41564-024-01909-1","DOIUrl":"10.1038/s41564-024-01909-1","url":null,"abstract":"The hurdle for infection of human cells by many animal and insect viruses remains poorly understood. A study using a large-scale functional screening approach suggests that the entry step may be a lower barrier to zoonosis than previously anticipated.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"272-273"},"PeriodicalIF":20.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987465","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 : 2025-01-15DOI: 10.1038/s41564-024-01908-2
Jinying Shen, Jing Li, Quan Shen, Jihuan Hou, Chunhe Zhang, Haiqing Bai, Xiaoni Ai, Yinlei Su, Zihao Wang, Yunfei Zhang, Beibei Xu, Jiawei Hao, Ping Wang, Qisi Zhang, Adam Yongxin Ye, Zhen Li, Tang Feng, Le Li, Fei Qi, Qikai Wang, Yacong Sun, Chengyao Liu, Xuetong Xi, Lei Yan, Hanhui Hong, Yuting Chen, Xin Xie, Jing Xie, Xiaoheng Liu, Ruikun Du, Roberto Plebani, Lihe Zhang, Demin Zhou, George Church, Longlong Si
Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens. Diverse cellular E3 ubiquitin ligase–degron pairs are used to generate live attenuated influenza vaccines. Attenuation and humoral, mucosal and cellular immune responses were characterized in mouse and ferret models.
{"title":"Proteolysis-targeting influenza vaccine strains induce broad-spectrum immunity and in vivo protection","authors":"Jinying Shen, Jing Li, Quan Shen, Jihuan Hou, Chunhe Zhang, Haiqing Bai, Xiaoni Ai, Yinlei Su, Zihao Wang, Yunfei Zhang, Beibei Xu, Jiawei Hao, Ping Wang, Qisi Zhang, Adam Yongxin Ye, Zhen Li, Tang Feng, Le Li, Fei Qi, Qikai Wang, Yacong Sun, Chengyao Liu, Xuetong Xi, Lei Yan, Hanhui Hong, Yuting Chen, Xin Xie, Jing Xie, Xiaoheng Liu, Ruikun Du, Roberto Plebani, Lihe Zhang, Demin Zhou, George Church, Longlong Si","doi":"10.1038/s41564-024-01908-2","DOIUrl":"10.1038/s41564-024-01908-2","url":null,"abstract":"Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens. Diverse cellular E3 ubiquitin ligase–degron pairs are used to generate live attenuated influenza vaccines. Attenuation and humoral, mucosal and cellular immune responses were characterized in mouse and ferret models.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"431-447"},"PeriodicalIF":20.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981359","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 : 2025-01-13DOI: 10.1038/s41564-024-01891-8
Lejla Daruka, Márton Simon Czikkely, Petra Szili, Zoltán Farkas, Dávid Balogh, Gábor Grézal, Elvin Maharramov, Thu-Hien Vu, Levente Sipos, Szilvia Juhász, Anett Dunai, Andreea Daraba, Mónika Számel, Tóbiás Sári, Tamás Stirling, Bálint Márk Vásárhelyi, Eszter Ari, Chryso Christodoulou, Máté Manczinger, Márton Zsolt Enyedi, Gábor Jaksa, Károly Kovács, Stineke van Houte, Elizabeth Pursey, Lajos Pintér, Lajos Haracska, Bálint Kintses, Balázs Papp, Csaba Pál
Despite ongoing antibiotic development, evolution of resistance may render candidate antibiotics ineffective. Here we studied in vitro emergence of resistance to 13 antibiotics introduced after 2017 or currently in development, compared with in-use antibiotics. Laboratory evolution showed that clinically relevant resistance arises within 60 days of antibiotic exposure in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, priority Gram-negative ESKAPE pathogens. Resistance mutations are already present in natural populations of pathogens, indicating that resistance in nature can emerge through selection of pre-existing bacterial variants. Functional metagenomics showed that mobile resistance genes to antibiotic candidates are prevalent in clinical bacterial isolates, soil and human gut microbiomes. Overall, antibiotic candidates show similar susceptibility to resistance development as antibiotics currently in use, and the corresponding resistance mechanisms overlap. However, certain combinations of antibiotics and bacterial strains were less prone to developing resistance, revealing potential narrow-spectrum antibacterial therapies that could remain effective. Finally, we develop criteria to guide efforts in developing effective antibiotic candidates. An extensive experimental analysis of resistance to antibiotics in development or introduced post-2017 in ESKAPE bacteria reveals the dynamics of resistance acquisition, mutational targets and the presence of mutations in clinical and environmental isolates.
{"title":"ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro","authors":"Lejla Daruka, Márton Simon Czikkely, Petra Szili, Zoltán Farkas, Dávid Balogh, Gábor Grézal, Elvin Maharramov, Thu-Hien Vu, Levente Sipos, Szilvia Juhász, Anett Dunai, Andreea Daraba, Mónika Számel, Tóbiás Sári, Tamás Stirling, Bálint Márk Vásárhelyi, Eszter Ari, Chryso Christodoulou, Máté Manczinger, Márton Zsolt Enyedi, Gábor Jaksa, Károly Kovács, Stineke van Houte, Elizabeth Pursey, Lajos Pintér, Lajos Haracska, Bálint Kintses, Balázs Papp, Csaba Pál","doi":"10.1038/s41564-024-01891-8","DOIUrl":"10.1038/s41564-024-01891-8","url":null,"abstract":"Despite ongoing antibiotic development, evolution of resistance may render candidate antibiotics ineffective. Here we studied in vitro emergence of resistance to 13 antibiotics introduced after 2017 or currently in development, compared with in-use antibiotics. Laboratory evolution showed that clinically relevant resistance arises within 60 days of antibiotic exposure in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, priority Gram-negative ESKAPE pathogens. Resistance mutations are already present in natural populations of pathogens, indicating that resistance in nature can emerge through selection of pre-existing bacterial variants. Functional metagenomics showed that mobile resistance genes to antibiotic candidates are prevalent in clinical bacterial isolates, soil and human gut microbiomes. Overall, antibiotic candidates show similar susceptibility to resistance development as antibiotics currently in use, and the corresponding resistance mechanisms overlap. However, certain combinations of antibiotics and bacterial strains were less prone to developing resistance, revealing potential narrow-spectrum antibacterial therapies that could remain effective. Finally, we develop criteria to guide efforts in developing effective antibiotic candidates. An extensive experimental analysis of resistance to antibiotics in development or introduced post-2017 in ESKAPE bacteria reveals the dynamics of resistance acquisition, mutational targets and the presence of mutations in clinical and environmental isolates.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"313-331"},"PeriodicalIF":20.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01891-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967973","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}
Sugar preference is a key contributor to the overconsumption of sugar and the concomitant increase in the incidence of diabetes. However, the exact mechanism of its development remains ambiguous. Here we show that the expression of free fatty acid receptor Ffar4, a receptor for long-chain fatty acids, is decreased in patients and mouse models with diabetes, which is associated with high sugar intake. Deletion of intestinal Ffar4 in mice resulted in reduced gut Bacteroides vulgatus and its metabolite pantothenate, leading to dietary sugar preference. Pantothenate promoted the secretion of GLP-1 which inhibited sugar preference by stimulating hepatic FGF21 release, which in turn regulates energy metabolism. These findings uncover a previously unappreciated role of Ffar4 in negatively regulating sugar preference and suggest B. vulgatus-derived pantothenate as a potential therapeutic target for diabetes. Bacteroides vulgatus, a gut bacterium, promotes GLP-1 secretion through its metabolite, pantothenate, inhibiting sugar preference in mice.
{"title":"Free fatty acid receptor 4 modulates dietary sugar preference via the gut microbiota","authors":"Tingting Zhang, Wei Wang, Jiayu Li, Xianlong Ye, Zhe Wang, Siyuan Cui, Shiwei Shen, Xinmiao Liang, Yong Q. Chen, Shenglong Zhu","doi":"10.1038/s41564-024-01902-8","DOIUrl":"10.1038/s41564-024-01902-8","url":null,"abstract":"Sugar preference is a key contributor to the overconsumption of sugar and the concomitant increase in the incidence of diabetes. However, the exact mechanism of its development remains ambiguous. Here we show that the expression of free fatty acid receptor Ffar4, a receptor for long-chain fatty acids, is decreased in patients and mouse models with diabetes, which is associated with high sugar intake. Deletion of intestinal Ffar4 in mice resulted in reduced gut Bacteroides vulgatus and its metabolite pantothenate, leading to dietary sugar preference. Pantothenate promoted the secretion of GLP-1 which inhibited sugar preference by stimulating hepatic FGF21 release, which in turn regulates energy metabolism. These findings uncover a previously unappreciated role of Ffar4 in negatively regulating sugar preference and suggest B. vulgatus-derived pantothenate as a potential therapeutic target for diabetes. Bacteroides vulgatus, a gut bacterium, promotes GLP-1 secretion through its metabolite, pantothenate, inhibiting sugar preference in mice.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"348-361"},"PeriodicalIF":20.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974797","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 : 2025-01-10DOI: 10.1038/s41564-024-01912-6
Qi Yin, Ana C. da Silva, Francisco Zorrilla, Ana S. Almeida, Kiran R. Patil, Alexandre Almeida
Gut bacteria from the Enterobacteriaceae family are a major cause of opportunistic infections worldwide. Given their prevalence among healthy human gut microbiomes, interspecies interactions may play a role in modulating infection resistance. Here we uncover global ecological patterns linked to Enterobacteriaceae colonization and abundance by leveraging a large-scale dataset of 12,238 public human gut metagenomes spanning 45 countries. Machine learning analyses identified a robust gut microbiome signature associated with Enterobacteriaceae colonization status, consistent across health states and geographic locations. We classified 172 gut microbial species as co-colonizers and 135 as co-excluders, revealing a genus-wide signal of colonization resistance within Faecalibacterium and strain-specific co-colonization patterns of the underexplored Faecalimonas phoceensis. Co-exclusion is linked to functions involved in short-chain fatty acid production, iron metabolism and quorum sensing, while co-colonization is linked to greater functional diversity and metabolic resemblance to Enterobacteriaceae. Our work underscores the critical role of the intestinal environment in the colonization success of gut-associated opportunistic pathogens with implications for developing non-antibiotic therapeutic strategies. Assessing more than 12,000 metagenomic samples from across the world using computational approaches, the authors determined interactions between species that co-colonize or co-exclude Enterobacteriaceae in terms of functional pathways and metabolites in healthy human gut microbiomes.
{"title":"Ecological dynamics of Enterobacteriaceae in the human gut microbiome across global populations","authors":"Qi Yin, Ana C. da Silva, Francisco Zorrilla, Ana S. Almeida, Kiran R. Patil, Alexandre Almeida","doi":"10.1038/s41564-024-01912-6","DOIUrl":"10.1038/s41564-024-01912-6","url":null,"abstract":"Gut bacteria from the Enterobacteriaceae family are a major cause of opportunistic infections worldwide. Given their prevalence among healthy human gut microbiomes, interspecies interactions may play a role in modulating infection resistance. Here we uncover global ecological patterns linked to Enterobacteriaceae colonization and abundance by leveraging a large-scale dataset of 12,238 public human gut metagenomes spanning 45 countries. Machine learning analyses identified a robust gut microbiome signature associated with Enterobacteriaceae colonization status, consistent across health states and geographic locations. We classified 172 gut microbial species as co-colonizers and 135 as co-excluders, revealing a genus-wide signal of colonization resistance within Faecalibacterium and strain-specific co-colonization patterns of the underexplored Faecalimonas phoceensis. Co-exclusion is linked to functions involved in short-chain fatty acid production, iron metabolism and quorum sensing, while co-colonization is linked to greater functional diversity and metabolic resemblance to Enterobacteriaceae. Our work underscores the critical role of the intestinal environment in the colonization success of gut-associated opportunistic pathogens with implications for developing non-antibiotic therapeutic strategies. Assessing more than 12,000 metagenomic samples from across the world using computational approaches, the authors determined interactions between species that co-colonize or co-exclude Enterobacteriaceae in terms of functional pathways and metabolites in healthy human gut microbiomes.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 2","pages":"541-553"},"PeriodicalIF":20.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41564-024-01912-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961335","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 : 2025-01-10DOI: 10.1038/s41564-024-01913-5
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
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.
{"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}
Pub Date : 2025-01-10DOI: 10.1038/s41564-024-01903-7
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
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.
{"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}
Pub Date : 2025-01-10DOI: 10.1038/s41564-024-01895-4
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
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.
{"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}
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