Nitzan Aframian, Shira Omer Bendori, Tal Hen, Polina Guler, Avigdor Eldar
{"title":"Expression level of anti-phage defence systems controls a trade-off between protection range and autoimmunity","authors":"Nitzan Aframian, Shira Omer Bendori, Tal Hen, Polina Guler, Avigdor Eldar","doi":"10.1038/s41564-025-02063-y","DOIUrl":"10.1038/s41564-025-02063-y","url":null,"abstract":"The evolutionary arms race between bacteria and phages has given rise to elaborate anti-phage defence mechanisms. Although many of these systems have been characterized at the molecular level, the general principles and constraints at play are underexplored. It is broadly recognized that in addition to the protection they provide, these systems also bear a substantial cost. Here we identify an expression-dependent trade-off between the protection range of defence systems and the fitness burden they impose. We first focus on the SpbK system of Bacillus subtilis and then generalize to other systems across a range of bacteria. We show that increasing expression of defence systems enhances their protection range, and provide evidence that this is achieved by overwhelming phage strategies for circumventing bacterial defence. However, for most systems tested, increased expression also leads to self-inflicted toxicity. This trade-off between protection and autoimmunity may shape the evolution of regulatory strategies and favour the coexistence of multiple systems within a single genome. The authors examine several defense systems and find that increased expression enhances their protection range, albeit at a cost of autoimmunity.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1954-1962"},"PeriodicalIF":19.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701416","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}
Rebecca J. Carlson, J. J. Patten, George Stefanakis, Brian Y. Soong, Adityanarayanan Radhakrishnan, Avtar Singh, Naveen Thakur, Kathleen C. F. Sheehan, Gaya K. Amarasinghe, Nir Hacohen, Christopher F. Basler, Daisy W. Leung, Caroline Uhler, Robert A. Davey, Paul C. Blainey
{"title":"Single-cell image-based screens identify host regulators of Ebola virus infection dynamics","authors":"Rebecca J. Carlson, J. J. Patten, George Stefanakis, Brian Y. Soong, Adityanarayanan Radhakrishnan, Avtar Singh, Naveen Thakur, Kathleen C. F. Sheehan, Gaya K. Amarasinghe, Nir Hacohen, Christopher F. Basler, Daisy W. Leung, Caroline Uhler, Robert A. Davey, Paul C. Blainey","doi":"10.1038/s41564-025-02034-3","DOIUrl":"10.1038/s41564-025-02034-3","url":null,"abstract":"Filoviruses such as Ebola virus (EBOV) give rise to frequent epidemics with high case fatality rates while therapeutic options remain limited. Earlier genetic screens aimed to identify potential drug targets for EBOV relied on systems that may not fully recapitulate the virus life cycle. Here we applied an image-based genome-wide CRISPR screen to identify 998 host regulators of EBOV infection in 39,085,093 cells. A deep learning model associated each host factor with a distinct viral replication step. From this we confirmed UQCRB as a post-entry regulator of EBOV RNA replication and show that small-molecule UQCRB inhibition reduced virus infection in vitro. Using a random forest model, we found that perturbations on STRAP (a spliceosome-associated factor) disrupted the equilibrium between viral RNA and protein. STRAP was associated with VP35, a viral RNA processing protein. This genome-wide screen coupled with 12 secondary screens including validation experiments with Sudan and Marburg virus, presents a rich resource for host regulators of virus replication and potential targets for therapeutic intervention. A single-cell resolution image-based genome-wide CRISPR screen, analysed with deep learning and random forest models, identified host factors regulating Ebola virus infection at distinct stages in the viral life cycle.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1989-2002"},"PeriodicalIF":19.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694062","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}
Mantas Sereika, Aaron James Mussig, Chenjing Jiang, Kalinka Sand Knudsen, Thomas Bygh Nymann Jensen, Francesca Petriglieri, Yu Yang, Vibeke Rudkjøbing Jørgensen, Francesco Delogu, Emil Aarre Sørensen, Per Halkjær Nielsen, Caitlin Margaret Singleton, Philip Hugenholtz, Mads Albertsen
{"title":"Genome-resolved long-read sequencing expands known microbial diversity across terrestrial habitats","authors":"Mantas Sereika, Aaron James Mussig, Chenjing Jiang, Kalinka Sand Knudsen, Thomas Bygh Nymann Jensen, Francesca Petriglieri, Yu Yang, Vibeke Rudkjøbing Jørgensen, Francesco Delogu, Emil Aarre Sørensen, Per Halkjær Nielsen, Caitlin Margaret Singleton, Philip Hugenholtz, Mads Albertsen","doi":"10.1038/s41564-025-02062-z","DOIUrl":"10.1038/s41564-025-02062-z","url":null,"abstract":"The emergence of high-throughput, long-read DNA sequencing has enabled recovery of microbial genomes from environmental samples at scale. However, expanding the terrestrial microbial genome catalogue has been challenging due to the enormous complexity of these environments. Here we performed deep, long-read Nanopore sequencing of 154 soil and sediment samples collected during the Microflora Danica project, yielding genomes of 15,314 previously undescribed microbial species, recovered using our custom mmlong2 workflow. The recovered microbial genomes span 1,086 previously uncharacterized genera and expand the phylogenetic diversity of the prokaryotic tree of life by 8%. The long-read assemblies also enabled the recovery of thousands of complete ribosomal RNA operons, biosynthetic gene clusters and CRISPR-Cas systems. Furthermore, the incorporation of the recovered genomes into public genomic databases substantially improved species-level classification rates for soil and sediment metagenomic datasets. These findings demonstrate that long-read sequencing allows cost-effective recovery of high-quality microbial genomes from highly complex ecosystems, which remain an untapped source of biodiversity. Nanopore sequencing of Danish soils and sediments yields genomes from over 15,000 microbial species, expanding the phylogenetic diversity of prokaryotes by 8%.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"2018-2030"},"PeriodicalIF":19.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02062-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694063","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}
Tianliang Li, Ligang Kong, Xinghui Li, Sijin Wu, Kuldeep S. Attri, Yan Li, Weipeng Gong, Bao Zhao, Lupeng Li, Laura E. Herring, John M. Asara, Lei Xu, Xiaobo Luo, Yu L. Lei, Qin Ma, Stephanie Seveau, John S. Gunn, Xiaolin Cheng, Pankaj K. Singh, Douglas R. Green, Haibo Wang, Haitao Wen
{"title":"Retraction Note: Listeria monocytogenes upregulates mitochondrial calcium signalling to inhibit LC3-associated phagocytosis as a survival strategy","authors":"Tianliang Li, Ligang Kong, Xinghui Li, Sijin Wu, Kuldeep S. Attri, Yan Li, Weipeng Gong, Bao Zhao, Lupeng Li, Laura E. Herring, John M. Asara, Lei Xu, Xiaobo Luo, Yu L. Lei, Qin Ma, Stephanie Seveau, John S. Gunn, Xiaolin Cheng, Pankaj K. Singh, Douglas R. Green, Haibo Wang, Haitao Wen","doi":"10.1038/s41564-025-02081-w","DOIUrl":"10.1038/s41564-025-02081-w","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 9","pages":"2354-2354"},"PeriodicalIF":19.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02081-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684449","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}
Aleksandr A. Arzamasov, Dmitry A. Rodionov, Matthew C. Hibberd, Janaki L. Guruge, James E. Kent, Marat D. Kazanov, Semen A. Leyn, Marinela L. Elane, Kristija Sejane, Annalee Furst, Lars Bode, Michael J. Barratt, Jeffrey I. Gordon, Andrei L. Osterman
{"title":"Integrative genomic reconstruction reveals heterogeneity in carbohydrate utilization across human gut bifidobacteria","authors":"Aleksandr A. Arzamasov, Dmitry A. Rodionov, Matthew C. Hibberd, Janaki L. Guruge, James E. Kent, Marat D. Kazanov, Semen A. Leyn, Marinela L. Elane, Kristija Sejane, Annalee Furst, Lars Bode, Michael J. Barratt, Jeffrey I. Gordon, Andrei L. Osterman","doi":"10.1038/s41564-025-02056-x","DOIUrl":"10.1038/s41564-025-02056-x","url":null,"abstract":"Bifidobacteria are beneficial saccharolytic microbes that are widely used as probiotics or in synbiotic formulations, yet individual responses to supplementation can vary with strain type, microbiota composition, diet and lifestyle, underscoring the need for strain-level insights into glycan metabolism. Here we reconstructed 68 pathways for the utilization of mono-, di-, oligo- and polysaccharides by analysing the distribution of 589 curated metabolic gene functions (catabolic enzymes, transporters and transcriptional regulators) across 3,083 non-redundant Bifidobacterium genomes of human origin. Thirty-eight predicted phenotypes were validated in vitro for 30 geographically diverse strains, supporting genomics-based predictions. Our analysis uncovered extensive inter- and intraspecies functional heterogeneity, including a distinct clade within Bifidobacterium longum that metabolizes α-glucans and Bangladeshi isolates carrying unique gene clusters for xyloglucan and human milk oligosaccharide utilization. This large-scale genomic compendium advances our understanding of bifidobacterial carbohydrate metabolism and can inform the rational design of probiotic and synbiotic formulations tailored to strain-specific nutrient preferences. A comprehensive genomic analysis reveals species- and strain-level heterogeneity in carbohydrate utilization potential across bifidobacteria of human origin.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"2031-2047"},"PeriodicalIF":19.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02056-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640383","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":"Fighting malaria as a patient and scientist","authors":"Fitsum Girma Tadesse","doi":"10.1038/s41564-025-02052-1","DOIUrl":"10.1038/s41564-025-02052-1","url":null,"abstract":"Fitsum Tadesse was infected with malaria as a young child in Ethiopia and faced challenges to access efficacious treatment during a time of widespread drug resistance. Today, as a scientist in Africa, the fight against Plasmodium falciparum is his prime research goal.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1793-1794"},"PeriodicalIF":19.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629706","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}
Tina Drobnič, Eli J. Cohen, Thomas Calcraft, Mona Alzheimer, Kathrin Froschauer, Sarah Svensson, William H. Hoffmann, Nanki Singh, Sriram G. Garg, Louie D. Henderson, Trishant R. Umrekar, Andrea Nans, Deborah Ribardo, Francesco Pedaci, Ashley L. Nord, Georg K. A. Hochberg, David R. Hendrixson, Cynthia M. Sharma, Peter B. Rosenthal, Morgan Beeby
{"title":"Author Correction: In situ structure of a bacterial flagellar motor at subnanometre resolution reveals adaptations for increased torque","authors":"Tina Drobnič, Eli J. Cohen, Thomas Calcraft, Mona Alzheimer, Kathrin Froschauer, Sarah Svensson, William H. Hoffmann, Nanki Singh, Sriram G. Garg, Louie D. Henderson, Trishant R. Umrekar, Andrea Nans, Deborah Ribardo, Francesco Pedaci, Ashley L. Nord, Georg K. A. Hochberg, David R. Hendrixson, Cynthia M. Sharma, Peter B. Rosenthal, Morgan Beeby","doi":"10.1038/s41564-025-02082-9","DOIUrl":"10.1038/s41564-025-02082-9","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"2092-2092"},"PeriodicalIF":19.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02082-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622385","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}
Aline Sardinha-Silva, Pedro H. Gazzinelli-Guimaraes, Oluwaremilekun G. Ajakaye, Fabricio M. S. Oliveira, Tiago R. Ferreira, Eliza V. C. Alves-Ferreira, Erick T. Tjhin, Beth Gregg, Marc Y. Fink, Camila H. Coelho, Steven M. Singer, Michael E. Grigg
{"title":"Giardia-induced Type 2 mucosal immunity attenuates intestinal inflammation caused by co-infection or colitis in mice","authors":"Aline Sardinha-Silva, Pedro H. Gazzinelli-Guimaraes, Oluwaremilekun G. Ajakaye, Fabricio M. S. Oliveira, Tiago R. Ferreira, Eliza V. C. Alves-Ferreira, Erick T. Tjhin, Beth Gregg, Marc Y. Fink, Camila H. Coelho, Steven M. Singer, Michael E. Grigg","doi":"10.1038/s41564-025-02051-2","DOIUrl":"10.1038/s41564-025-02051-2","url":null,"abstract":"Diarrhoeal diseases are the second leading cause of death in children worldwide. Epidemiological studies show that co-infection with the protozoan parasite Giardia intestinalis decreases diarrhoeal severity. Here we show a high incidence of asymptomatic Giardia infection in school-aged children from Nigeria. In a mouse model, Giardia induced a Type 2 mucosal immune response, characterized by antigen-specific Th2 cells, IL-25, Type 2 cytokines, and goblet cell hyperplasia. Single-cell RNA sequencing and multiparameter flow cytometry revealed expansion of IL-10-producing Th2 cells, which promoted parasite persistence and protected against Toxoplasma gondii-induced ileitis and dextran sulfate sodium-induced colitis. This protective effect was STAT6 dependent, as IL-4R blockade or STAT6 deficiency impaired IL-10+ Th2 responses, resulting in Th1/Th17-driven tissue damage, inflammation and clearance of Giardia infection. Our findings demonstrate that Giardia reshapes mucosal immunity toward a Type 2 response, facilitating parasitism and conferring mutualistic protection from inflammatory pathologies, highlighting a key role for protists in mucosal defence regulation. A host–protist interaction regulates mucosal immunity to promote parasitism which also reduces the risk of inflammatory-driven pathologies of the gut.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1886-1901"},"PeriodicalIF":19.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578397","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}
Jiayu Zhang, Elizabeth C. Chavez, Melina Winkler, Jianche Liu, Sebastian Carver, Aaron E. Lin, Abhishek Biswas, Tomokazu Tamura, Anna Tseng, Danyang Wang, Aaron Benhamou, Aoife K. O’ Connell, Mao Matsuo, Jack E. Norton, Devin Kenney, Britt Adamson, Ralph E. Kleiner, Benjamin Burwitz, Nicholas A. Crossland, Florian Douam, Alexander Ploss
{"title":"Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine","authors":"Jiayu Zhang, Elizabeth C. Chavez, Melina Winkler, Jianche Liu, Sebastian Carver, Aaron E. Lin, Abhishek Biswas, Tomokazu Tamura, Anna Tseng, Danyang Wang, Aaron Benhamou, Aoife K. O’ Connell, Mao Matsuo, Jack E. Norton, Devin Kenney, Britt Adamson, Ralph E. Kleiner, Benjamin Burwitz, Nicholas A. Crossland, Florian Douam, Alexander Ploss","doi":"10.1038/s41564-025-02047-y","DOIUrl":"10.1038/s41564-025-02047-y","url":null,"abstract":"The live-attenuated yellow fever 17D vaccine strain differs genetically only minimally from its virulent parent. However, it remains unclear which sequence differences lead to virulence or attenuation. Here we demonstrate, using SHAPE-MaP, that these mutations do not induce global RNA structure changes and show that protein sequence mutations are mostly responsible for the phenotypic differences between 17D and virulent YFV. Using a highly modular, combinatorial genetic approach, we identified key mutations in the envelope (E) and non-structural 2A (NS2A) proteins that increase 17D’s ability to spread and enhance host antiviral responses. Introducing these mutations into infectious clones of virulent YFV genomes results in viral attenuation in vitro and in two mouse models. Collectively, our results define the genetic basis for 17D attenuation and highlight a potentially general approach for creating live-attenuated vaccines by introducing mutations resulting in similar phenotypic changes in other pathogenic viruses. Amino acid changes in the envelope and non-structural 2A protein attenuate the virulent yellow fever virus (YFV) and enhance host antiviral responses upon infection in vivo. These traits explain the potency of the YFV vaccine.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1902-1917"},"PeriodicalIF":19.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02047-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578128","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}
Zhen Hou, Yao Shen, Stanley Fronik, Juan Shen, Jiong Shi, Jialu Xu, Long Chen, Nathan Hardenbrook, Alan N. Engelman, Christopher Aiken, Peijun Zhang
{"title":"HIV-1 nuclear import is selective and depends on both capsid elasticity and nuclear pore adaptability","authors":"Zhen Hou, Yao Shen, Stanley Fronik, Juan Shen, Jiong Shi, Jialu Xu, Long Chen, Nathan Hardenbrook, Alan N. Engelman, Christopher Aiken, Peijun Zhang","doi":"10.1038/s41564-025-02054-z","DOIUrl":"10.1038/s41564-025-02054-z","url":null,"abstract":"Lentiviruses, such as HIV-1, infect non-dividing cells by traversing the nuclear pore complex (NPC); however, the detailed molecular processes remain unclear. Here we reconstituted functional HIV-1 nuclear import using permeabilized T cells and isolated HIV-1 cores, which significantly increases import events, and developed an integrated three-dimensional cryo-correlative workflow to specifically target and image 1,489 native HIV-1 cores at 4 distinct nuclear import stages using cryo-electron tomography. We found HIV-1 nuclear import depends on both capsid elasticity and nuclear pore adaptability. The NPC acts as a selective filter, preferentially importing smaller cores, while expanding and deforming to accommodate their passage. Brittle mutant cores fail to enter the NPC, while CPSF6-binding-deficient cores enter but stall within the NPC, leading to impaired nuclear import. This study uncovers the interplay between the HIV-1 core and the NPC and provides a framework to dissect HIV-1 nuclear import and downstream events, such as uncoating and integration. By developing a functional nuclear import system and correlative imaging workflow, this study reveals that HIV-1 nuclear entry relies on the elasticity of both the viral capsid and the nuclear pore to enable the selective passage of small HIV-1 cores.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 8","pages":"1868-1885"},"PeriodicalIF":19.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02054-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568943","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}
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