Pub Date : 2025-11-11DOI: 10.1038/s41564-025-02178-2
Katie A. Johnson, Hemant N. Goswami, Ryan J. Catchpole, Fozieh Ahmadizadeh, Peng Zhao, Lance Wells, Hong Li, Michael P. Terns
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems provide powerful adaptive immunity against phage infection. In response, phages use anti-CRISPR (Acr) proteins to evade CRISPR immunity. The few type III Acrs identified so far show conditional effectiveness in countering type III immunity or rely on unknown or poorly understood inhibitory mechanisms. Here we report the discovery of AcrIIIA2, a type III-A Acr encoded by Streptococcus thermophilus phages. Biochemical and structural analyses reveal that phage AcrIIIA2 co-opts host enolase, a highly abundant glycolysis enzyme, to form a ternary complex with the S. thermophilus type III-A (Csm) CRISPR ribonucleoprotein complex, obstructing its immune responses. The enolase-chaperoned AcrIIIA2 blocks the initial step of phage RNA binding, thereby preventing downstream type III anti-phage immune responses. Enolase participates in the anti-immune response by serving as an essential structural scaffold, stabilizing Acr–CRISPR interactions. These findings uncover a new anti-defence strategy that exploits a well-conserved host factor to block CRISPR immunity. Streptococcus thermophilus phages circumvent host CRISPR defences via AcrIIIA2, which complexes with enolase, a highly abundant glycolysis enzyme, to block phage RNA binding.
CRISPR （Clustered Regularly Interspaced Short Palindromic Repeats）系统为噬菌体感染提供了强大的适应性免疫。作为回应，噬菌体使用抗CRISPR （Acr）蛋白来逃避CRISPR免疫。迄今发现的少数III型Acrs在对抗III型免疫方面表现出有条件的有效性，或依赖于未知或知之甚少的抑制机制。本文报道了嗜热链球菌噬菌体编码的III-A型Acr AcrIIIA2的发现。生化和结构分析表明，噬菌体AcrIIIA2与宿主烯醇化酶（一种丰富的糖酵解酶）形成三元复合物，与嗜热链球菌III-A型（Csm） CRISPR核糖核蛋白复合物形成三元复合物，阻碍其免疫应答。烯醇酶伴随的AcrIIIA2阻断了噬菌体RNA结合的初始步骤，从而阻止了下游III型抗噬菌体免疫反应。烯醇化酶参与抗免疫反应，作为一个必要的结构支架，稳定Acr-CRISPR相互作用。这些发现揭示了一种新的抗防御策略，它利用一种保存良好的宿主因子来阻断CRISPR免疫。嗜热链球菌噬菌体通过与烯醇化酶（一种高度丰富的糖酵解酶）复合物的AcrIIIA2绕过宿主CRISPR防御，阻断噬菌体RNA结合。
{"title":"A phage-encoded anti-CRISPR protein co-opts host enolase to prevent type III CRISPR immunity","authors":"Katie A. Johnson, Hemant N. Goswami, Ryan J. Catchpole, Fozieh Ahmadizadeh, Peng Zhao, Lance Wells, Hong Li, Michael P. Terns","doi":"10.1038/s41564-025-02178-2","DOIUrl":"10.1038/s41564-025-02178-2","url":null,"abstract":"CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems provide powerful adaptive immunity against phage infection. In response, phages use anti-CRISPR (Acr) proteins to evade CRISPR immunity. The few type III Acrs identified so far show conditional effectiveness in countering type III immunity or rely on unknown or poorly understood inhibitory mechanisms. Here we report the discovery of AcrIIIA2, a type III-A Acr encoded by Streptococcus thermophilus phages. Biochemical and structural analyses reveal that phage AcrIIIA2 co-opts host enolase, a highly abundant glycolysis enzyme, to form a ternary complex with the S. thermophilus type III-A (Csm) CRISPR ribonucleoprotein complex, obstructing its immune responses. The enolase-chaperoned AcrIIIA2 blocks the initial step of phage RNA binding, thereby preventing downstream type III anti-phage immune responses. Enolase participates in the anti-immune response by serving as an essential structural scaffold, stabilizing Acr–CRISPR interactions. These findings uncover a new anti-defence strategy that exploits a well-conserved host factor to block CRISPR immunity. Streptococcus thermophilus phages circumvent host CRISPR defences via AcrIIIA2, which complexes with enolase, a highly abundant glycolysis enzyme, to block phage RNA binding.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3162-3175"},"PeriodicalIF":19.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484869","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 : 2025-11-10DOI: 10.1038/s41564-025-02166-6
Seyed Davoud Jazayeri, Lisa Borkner, Caroline E. Sutton, Kingston H. G. Mills
The Gram-negative bacterium Bordetella pertussis causes whooping cough (pertussis), a severe respiratory disease, especially in young children, which is resurgent despite high vaccine coverage. The current acellular pertussis vaccine prevents severe disease but does not prevent nasal infection with B. pertussis. This parenterally delivered vaccine induces potent circulating antibody responses but limited respiratory tissue-resident memory T cells and IgA responses. Here we developed a vaccine approach based on respiratory delivery of antibiotic-inactivated B. pertussis (AIBP). Ciprofloxacin-treated B. pertussis potently activated antigen-presenting cells to drive T cell responses. AIBP immunization via aerosol or intranasal administration conferred a high level of protection against lung and nasal infection. The AIBP vaccine induced B. pertussis-specific interleukin (IL)-17-producing CD4 tissue-resident memory T cells that recruited neutrophils to the respiratory tract. Protection was abrogated by depletion of CD4 T cells or neutralization of IL-17 in mice. Unlike a parenterally delivered whole-cell pertussis vaccine, which induced high levels of serum IL-1β, IL-6, tumour necrosis factor and C-reactive protein, aerosol immunization with the AIBP vaccine did not promote systemic pro-inflammatory responses. We present preclinical evidence of a safe and effective respiratory-delivered vaccine platform for inducing T cell-mediated sterilizing immunity against a respiratory pathogen. In this preclinical study, the authors find that respiratory immunization with an antibiotic-treated bacterial vaccine is a highly effective approach for inducing tissue-resident memory T cells that protect against lung and nasal infection with Bordetella pertussis.
{"title":"Respiratory immunization using antibiotic-inactivated Bordetella pertussis confers T cell-mediated protection against nasal infection in mice","authors":"Seyed Davoud Jazayeri, Lisa Borkner, Caroline E. Sutton, Kingston H. G. Mills","doi":"10.1038/s41564-025-02166-6","DOIUrl":"10.1038/s41564-025-02166-6","url":null,"abstract":"The Gram-negative bacterium Bordetella pertussis causes whooping cough (pertussis), a severe respiratory disease, especially in young children, which is resurgent despite high vaccine coverage. The current acellular pertussis vaccine prevents severe disease but does not prevent nasal infection with B. pertussis. This parenterally delivered vaccine induces potent circulating antibody responses but limited respiratory tissue-resident memory T cells and IgA responses. Here we developed a vaccine approach based on respiratory delivery of antibiotic-inactivated B. pertussis (AIBP). Ciprofloxacin-treated B. pertussis potently activated antigen-presenting cells to drive T cell responses. AIBP immunization via aerosol or intranasal administration conferred a high level of protection against lung and nasal infection. The AIBP vaccine induced B. pertussis-specific interleukin (IL)-17-producing CD4 tissue-resident memory T cells that recruited neutrophils to the respiratory tract. Protection was abrogated by depletion of CD4 T cells or neutralization of IL-17 in mice. Unlike a parenterally delivered whole-cell pertussis vaccine, which induced high levels of serum IL-1β, IL-6, tumour necrosis factor and C-reactive protein, aerosol immunization with the AIBP vaccine did not promote systemic pro-inflammatory responses. We present preclinical evidence of a safe and effective respiratory-delivered vaccine platform for inducing T cell-mediated sterilizing immunity against a respiratory pathogen. In this preclinical study, the authors find that respiratory immunization with an antibiotic-treated bacterial vaccine is a highly effective approach for inducing tissue-resident memory T cells that protect against lung and nasal infection with Bordetella pertussis.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3094-3106"},"PeriodicalIF":19.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02166-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145478140","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 : 2025-11-10DOI: 10.1038/s41564-025-02169-3
Ricardo da Silva Antunes, Alessandro Sette
A respiratory vaccine platform shows promise against pertussis (whooping cough) by providing sterilizing immunity and generating local mucosal immunity. This approach could potentially solve the inability of current vaccines to prevent transmission.
{"title":"New life into pertussis prevention","authors":"Ricardo da Silva Antunes, Alessandro Sette","doi":"10.1038/s41564-025-02169-3","DOIUrl":"10.1038/s41564-025-02169-3","url":null,"abstract":"A respiratory vaccine platform shows promise against pertussis (whooping cough) by providing sterilizing immunity and generating local mucosal immunity. This approach could potentially solve the inability of current vaccines to prevent transmission.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3045-3046"},"PeriodicalIF":19.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145478139","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 : 2025-11-07DOI: 10.1038/s41564-025-02162-w
Erik Bakkeren, Vit Piskovsky, Megan N. Y. Lee, Martin T. Jahn, Kevin R. Foster
Microorganisms commonly live in diverse communities where changes in composition can be critical for health, industry and the environment. Yet, what enables one strain to competitively replace another in these complex conditions remains poorly understood. Here we develop a mathematical model to determine general principles of strain displacement. Our modelling reveals that weak resource competition enables successful invasion while strong interference competition, for example, via antimicrobial production, enables successful displacement. We verify these predictions using in vitro assays with genetically engineered Escherichia coli. We then apply our principles to displace multidrug-resistant clinical isolates using strains that are equipped with a potent bacteriocin. Finally, we perform experiments with diverse human gut symbionts, which reveal that displacement relies on low resource competition not only between competing strains but also with the broader community, that is, limited nutrient blocking. These general rules for ecological success in microbial communities could be applied for targeted displacement of bacteria. Mathematical modelling and experimental tests reveal principles that govern displacement of a resident strain by an invader in microbial communities.
{"title":"Strain displacement in microbiomes via ecological competition","authors":"Erik Bakkeren, Vit Piskovsky, Megan N. Y. Lee, Martin T. Jahn, Kevin R. Foster","doi":"10.1038/s41564-025-02162-w","DOIUrl":"10.1038/s41564-025-02162-w","url":null,"abstract":"Microorganisms commonly live in diverse communities where changes in composition can be critical for health, industry and the environment. Yet, what enables one strain to competitively replace another in these complex conditions remains poorly understood. Here we develop a mathematical model to determine general principles of strain displacement. Our modelling reveals that weak resource competition enables successful invasion while strong interference competition, for example, via antimicrobial production, enables successful displacement. We verify these predictions using in vitro assays with genetically engineered Escherichia coli. We then apply our principles to displace multidrug-resistant clinical isolates using strains that are equipped with a potent bacteriocin. Finally, we perform experiments with diverse human gut symbionts, which reveal that displacement relies on low resource competition not only between competing strains but also with the broader community, that is, limited nutrient blocking. These general rules for ecological success in microbial communities could be applied for targeted displacement of bacteria. Mathematical modelling and experimental tests reveal principles that govern displacement of a resident strain by an invader in microbial communities.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3122-3135"},"PeriodicalIF":19.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02162-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455354","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 : 2025-11-06DOI: 10.1038/s41564-025-02180-8
Kira S. Makarova, Sergey A. Shmakov, Yuri I. Wolf, Pascal Mutz, Han Altae-Tran, Chase L. Beisel, Stan J. J. Brouns, Emmanuelle Charpentier, David Cheng, Jennifer Doudna, Daniel H. Haft, Philippe Horvath, Sylvain Moineau, Francisco J. M. Mojica, Patrick Pausch, Rafael Pinilla-Redondo, Shiraz A. Shah, Virginijus Siksnys, Michael P. Terns, Jesse Tordoff, Česlovas Venclovas, Malcolm F. White, Alexander F. Yakunin, Feng Zhang, Roger A. Garrett, Rolf Backofen, John van der Oost, Rodolphe Barrangou, Eugene V. Koonin
The known diversity of CRISPR–Cas systems continues to expand. To encompass new discoveries, here we present an updated evolutionary classification of CRISPR–Cas systems. The updated CRISPR–Cas classification includes 2 classes, 7 types and 46 subtypes, compared with the 6 types and 33 subtypes in our previous survey 5 years ago. In addition, a classification of the cyclic oligoadenylate-dependent signalling pathway in type III systems is presented. We also discuss recently characterized alternative CRISPR–Cas functionalities, notably, type IV variants that cleave the target DNA and type V variants that inhibit the target replication without cleavage. Analysis of the abundance of CRISPR–Cas variants in genomes and metagenomes shows that the previously defined systems are relatively common, whereas the more recently characterized variants are comparatively rare. These low abundance variants comprise the long tail of the CRISPR–Cas distribution in prokaryotes and their viruses, and remain to be characterized experimentally. An exploration of previously undescribed variants from the long tail of the CRISPR–Cas distribution.
{"title":"An updated evolutionary classification of CRISPR–Cas systems including rare variants","authors":"Kira S. Makarova, Sergey A. Shmakov, Yuri I. Wolf, Pascal Mutz, Han Altae-Tran, Chase L. Beisel, Stan J. J. Brouns, Emmanuelle Charpentier, David Cheng, Jennifer Doudna, Daniel H. Haft, Philippe Horvath, Sylvain Moineau, Francisco J. M. Mojica, Patrick Pausch, Rafael Pinilla-Redondo, Shiraz A. Shah, Virginijus Siksnys, Michael P. Terns, Jesse Tordoff, Česlovas Venclovas, Malcolm F. White, Alexander F. Yakunin, Feng Zhang, Roger A. Garrett, Rolf Backofen, John van der Oost, Rodolphe Barrangou, Eugene V. Koonin","doi":"10.1038/s41564-025-02180-8","DOIUrl":"10.1038/s41564-025-02180-8","url":null,"abstract":"The known diversity of CRISPR–Cas systems continues to expand. To encompass new discoveries, here we present an updated evolutionary classification of CRISPR–Cas systems. The updated CRISPR–Cas classification includes 2 classes, 7 types and 46 subtypes, compared with the 6 types and 33 subtypes in our previous survey 5 years ago. In addition, a classification of the cyclic oligoadenylate-dependent signalling pathway in type III systems is presented. We also discuss recently characterized alternative CRISPR–Cas functionalities, notably, type IV variants that cleave the target DNA and type V variants that inhibit the target replication without cleavage. Analysis of the abundance of CRISPR–Cas variants in genomes and metagenomes shows that the previously defined systems are relatively common, whereas the more recently characterized variants are comparatively rare. These low abundance variants comprise the long tail of the CRISPR–Cas distribution in prokaryotes and their viruses, and remain to be characterized experimentally. An exploration of previously undescribed variants from the long tail of the CRISPR–Cas distribution.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3346-3361"},"PeriodicalIF":19.4,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02180-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447673","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 : 2025-11-05DOI: 10.1038/s41564-025-02167-5
Alaina R. Weinheimer, Julia M. Brown, Brian Thompson, Greta Leonaviciene, Vaidotas Kiseliovas, Simonas Jocys, Jacob Munson-McGee, Gregory Gavelis, Corianna Mascena, Linas Mazutis, Nicole J. Poulton, Rapolas Zilionis, Ramunas Stepanauskas
Viruses and other extracellular genetic elements play essential roles in marine communities. However, methods to capture their full diversity remain limited by the constraints of bulk sequencing assemblers or pre-sorting throughput. Here we introduce environmental micro-compartment genomics (EMCG), which vastly improves the throughput and efficiency of single-particle genomic sequencing obtained from nanolitre volumes by compartmentalizing particles of a sample into picolitre-sized, semi-permeable capsules for in-capsule DNA amplification and barcoding. From 300 nanolitres of seawater, EMCG obtained genomic sequences of 2,037 particles. The microbiome composition agreed with other methods, and the virus-like assembly lengths indicated that most were near complete. Many viral assemblies belonged to the Naomiviridae, lacked metagenomic representation and aligned to outlier contigs of abundant, putative host lineages, suggesting their use of non-canonical DNA and overlooked ecological importance. This approach provides opportunities for high-throughput, quantitative and cost-effective genome analyses of individual cells and extracellular particles across complex microbiomes. Environmental micro-compartment genomics provides efficient and high-throughput single-particle DNA sequencing that captures overlooked members of microbial communities.
{"title":"Single-particle genomics uncovers abundant non-canonical marine viruses from nanolitre volumes","authors":"Alaina R. Weinheimer, Julia M. Brown, Brian Thompson, Greta Leonaviciene, Vaidotas Kiseliovas, Simonas Jocys, Jacob Munson-McGee, Gregory Gavelis, Corianna Mascena, Linas Mazutis, Nicole J. Poulton, Rapolas Zilionis, Ramunas Stepanauskas","doi":"10.1038/s41564-025-02167-5","DOIUrl":"10.1038/s41564-025-02167-5","url":null,"abstract":"Viruses and other extracellular genetic elements play essential roles in marine communities. However, methods to capture their full diversity remain limited by the constraints of bulk sequencing assemblers or pre-sorting throughput. Here we introduce environmental micro-compartment genomics (EMCG), which vastly improves the throughput and efficiency of single-particle genomic sequencing obtained from nanolitre volumes by compartmentalizing particles of a sample into picolitre-sized, semi-permeable capsules for in-capsule DNA amplification and barcoding. From 300 nanolitres of seawater, EMCG obtained genomic sequences of 2,037 particles. The microbiome composition agreed with other methods, and the virus-like assembly lengths indicated that most were near complete. Many viral assemblies belonged to the Naomiviridae, lacked metagenomic representation and aligned to outlier contigs of abundant, putative host lineages, suggesting their use of non-canonical DNA and overlooked ecological importance. This approach provides opportunities for high-throughput, quantitative and cost-effective genome analyses of individual cells and extracellular particles across complex microbiomes. Environmental micro-compartment genomics provides efficient and high-throughput single-particle DNA sequencing that captures overlooked members of microbial communities.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3245-3257"},"PeriodicalIF":19.4,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02167-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441127","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 : 2025-11-05DOI: 10.1038/s41564-025-02212-3
Laura A. Hug, Roland Hatzenpichler, Cristina Moraru, André R. Soares, Folker Meyer, Anke Heyder, The Data Reuse Consortium, Alexander J. Probst
{"title":"Author Correction: A roadmap for equitable reuse of public microbiome data","authors":"Laura A. Hug, Roland Hatzenpichler, Cristina Moraru, André R. Soares, Folker Meyer, Anke Heyder, The Data Reuse Consortium, Alexander J. Probst","doi":"10.1038/s41564-025-02212-3","DOIUrl":"10.1038/s41564-025-02212-3","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 1","pages":"335-335"},"PeriodicalIF":19.4,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02212-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452431","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 : 2025-11-04DOI: 10.1038/s41564-025-02168-4
Qing Yao, Alexandre Mercier, Arabinda Nayak, Lindsey May, Pui Yan Ho, Ariel Lewis-Ballester, Varsha Nair, Annapurna Sapre, Thomas Aeschbacher, Jit Mukherjee, Christopher Richards, Roberto Mateo, Aesop Cho, Eric Lansdon, Xinchao Yu
The herpes simplex virus (HSV) helicase–primase (HP) complex is a promising anti-herpes therapeutic target. However, progress in developing highly effective small-molecule HP inhibitors (HPIs) for the treatment of genital herpes has been hindered by the lack of structural information on the HP complex and the incomplete understanding of the mechanism of action of HPIs. Here we present the cryogenic electron microscopy structure of the HSV-1 HP apo-complex (3.8 Å), along with structures bound to pritelivir (3.2 Å) and amenamevir (3.2 Å)—two clinically active, chemically distinct HPIs. The potency of both inhibitors against HSV variants bearing mutations within the HPI binding pocket supports the high-resolution mapping of key molecular interactions while revealing residues that govern their antiviral spectrum against alphaherpesviruses. Our results provide important insight into the unique architecture of the HP complex and the mechanism of inhibition of HPIs, paving the way for the development of next-generation antivirals to treat herpesvirus infections. The cryo-EM structure of the herpes simplex virus helicase–primase (HP) complex informs about the mechanism of action of HP inhibitors pritelivir and amenamevir, which are drugs of clinical relevance.
{"title":"Structural and mechanistic insights into herpesvirus helicase–primase and its therapeutic inhibitors","authors":"Qing Yao, Alexandre Mercier, Arabinda Nayak, Lindsey May, Pui Yan Ho, Ariel Lewis-Ballester, Varsha Nair, Annapurna Sapre, Thomas Aeschbacher, Jit Mukherjee, Christopher Richards, Roberto Mateo, Aesop Cho, Eric Lansdon, Xinchao Yu","doi":"10.1038/s41564-025-02168-4","DOIUrl":"10.1038/s41564-025-02168-4","url":null,"abstract":"The herpes simplex virus (HSV) helicase–primase (HP) complex is a promising anti-herpes therapeutic target. However, progress in developing highly effective small-molecule HP inhibitors (HPIs) for the treatment of genital herpes has been hindered by the lack of structural information on the HP complex and the incomplete understanding of the mechanism of action of HPIs. Here we present the cryogenic electron microscopy structure of the HSV-1 HP apo-complex (3.8 Å), along with structures bound to pritelivir (3.2 Å) and amenamevir (3.2 Å)—two clinically active, chemically distinct HPIs. The potency of both inhibitors against HSV variants bearing mutations within the HPI binding pocket supports the high-resolution mapping of key molecular interactions while revealing residues that govern their antiviral spectrum against alphaherpesviruses. Our results provide important insight into the unique architecture of the HP complex and the mechanism of inhibition of HPIs, paving the way for the development of next-generation antivirals to treat herpesvirus infections. The cryo-EM structure of the herpes simplex virus helicase–primase (HP) complex informs about the mechanism of action of HP inhibitors pritelivir and amenamevir, which are drugs of clinical relevance.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3191-3201"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02168-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434688","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 : 2025-11-04DOI: 10.1038/s41564-025-02195-1
Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang
{"title":"Editorial Expression of Concern: Metabolic remodelling produces fumarate via the aspartate–argininosuccinate shunt in macrophages as an antiviral defence","authors":"Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang","doi":"10.1038/s41564-025-02195-1","DOIUrl":"10.1038/s41564-025-02195-1","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3365-3365"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02195-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434685","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 : 2025-10-31DOI: 10.1038/s41564-025-02171-9
Neil MacAlasdair, Anna K. Pöntinen, Clare Ling, Sudaraka Mallawaarachchi, Janjira Thaipadungpanit, Francois H. Nosten, Claudia Turner, Stephen D. Bentley, Nicholas J. Croucher, Paul Turner, Jukka Corander
Haemophilus influenzae is an opportunistic bacterial pathogen that causes both non-invasive and invasive disease in humans. Although the H. influenzae type b vaccine can reduce invasive disease, it is not effective against non-b serotypes or unencapsulated non-typeable H. influenzae (NTHi). The genetic population structure of H. influenzae, especially NTHi, which is typically prevalent in lower- and middle-income countries, is unclear. Here we whole-genome sequenced 4,474 isolates of H. influenzae from an unvaccinated paediatric carriage and pneumonia cohort from the Maela camp for displaced persons in northwestern Thailand. Despite no H. influenzae type b immunization, serotype b was uncommon, whereas 92.4% of the isolates were NTHi. Most multidrug-resistant lineages were NTHi, and there were no lineages enriched among disease samples. Incorporating 5,976 published genomes revealed a highly admixed population structure, low core genome nucleotide diversity and evidence of pervasive negative selection. Our findings expand our understanding of this major pathogen in lower- and middle-income countries and at a global scale. Large-scale sequencing and population genomic analyses reveal frequent transmission, a highly admixed global population structure and evidence of pervasive negative selection in Haemophilus influenzae.
{"title":"Genetic population structure of Haemophilus influenzae at local and global scales","authors":"Neil MacAlasdair, Anna K. Pöntinen, Clare Ling, Sudaraka Mallawaarachchi, Janjira Thaipadungpanit, Francois H. Nosten, Claudia Turner, Stephen D. Bentley, Nicholas J. Croucher, Paul Turner, Jukka Corander","doi":"10.1038/s41564-025-02171-9","DOIUrl":"10.1038/s41564-025-02171-9","url":null,"abstract":"Haemophilus influenzae is an opportunistic bacterial pathogen that causes both non-invasive and invasive disease in humans. Although the H. influenzae type b vaccine can reduce invasive disease, it is not effective against non-b serotypes or unencapsulated non-typeable H. influenzae (NTHi). The genetic population structure of H. influenzae, especially NTHi, which is typically prevalent in lower- and middle-income countries, is unclear. Here we whole-genome sequenced 4,474 isolates of H. influenzae from an unvaccinated paediatric carriage and pneumonia cohort from the Maela camp for displaced persons in northwestern Thailand. Despite no H. influenzae type b immunization, serotype b was uncommon, whereas 92.4% of the isolates were NTHi. Most multidrug-resistant lineages were NTHi, and there were no lineages enriched among disease samples. Incorporating 5,976 published genomes revealed a highly admixed population structure, low core genome nucleotide diversity and evidence of pervasive negative selection. Our findings expand our understanding of this major pathogen in lower- and middle-income countries and at a global scale. Large-scale sequencing and population genomic analyses reveal frequent transmission, a highly admixed global population structure and evidence of pervasive negative selection in Haemophilus influenzae.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"10 12","pages":"3136-3147"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02171-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404564","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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