Pub Date : 2026-02-06DOI: 10.1038/s41564-026-02267-w
Lejla Daruka, Petra Szili, Márton Simon Czikkely, Zoltán Farkas, Csaba Pál
{"title":"Addendum: ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro.","authors":"Lejla Daruka, Petra Szili, Márton Simon Czikkely, Zoltán Farkas, Csaba Pál","doi":"10.1038/s41564-026-02267-w","DOIUrl":"https://doi.org/10.1038/s41564-026-02267-w","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132301","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 : 2026-02-05DOI: 10.1038/s41564-026-02259-w
H Krukowski, S Valkenburg, A Vich Vila, L F Maciel, J F Vázquez-Castellanos, T Gryp, M Joossens, W Van Biesen, F Verbeke, M Derrien, G R B Huys, G Glorieux, J Raes
Despite recent progress, microbial associations reported in chronic kidney disease (CKD) remain inconsistent. Here we combined quantitative faecal metagenomics (n = 130) and cross-study biomarker comparisons (ntotal = 4,420) to study microbiome associations with estimated glomerular filtration rate (eGFR; kidney function) and 4-year CKD progression. Intestinal transit time (ITT) and medications significantly explained microbiome variation, surpassing eGFR-related effects. Lower eGFR was associated with increased p-cresol and indole biosynthetic potential and reduced plant-to-animal CAZyme ratios. This was consistent with community-wide saccharolytic-to-proteolytic microbiome transitions linked to dietary guidelines and slowed-down ITT. Peritoneal dialysis patients showed distinct microbiome dysbiosis accompanied by increased intestinal inflammation. Only Escherichia coli, an unnamed Alistipes species and Bifidobacterium adolescentis were covariate-independent markers for eGFR, but neither these nor previous microbial markers convincingly replicated across 11 studies. No predictors for CKD progression were found. Nevertheless, our study adds insight into plausible ITT and nutrition-related effects, highlighting their potential in CKD interventions.
{"title":"Host factors dictate gut microbiome alterations in chronic kidney disease more strongly than kidney function.","authors":"H Krukowski, S Valkenburg, A Vich Vila, L F Maciel, J F Vázquez-Castellanos, T Gryp, M Joossens, W Van Biesen, F Verbeke, M Derrien, G R B Huys, G Glorieux, J Raes","doi":"10.1038/s41564-026-02259-w","DOIUrl":"https://doi.org/10.1038/s41564-026-02259-w","url":null,"abstract":"<p><p>Despite recent progress, microbial associations reported in chronic kidney disease (CKD) remain inconsistent. Here we combined quantitative faecal metagenomics (n = 130) and cross-study biomarker comparisons (n<sub>total</sub> = 4,420) to study microbiome associations with estimated glomerular filtration rate (eGFR; kidney function) and 4-year CKD progression. Intestinal transit time (ITT) and medications significantly explained microbiome variation, surpassing eGFR-related effects. Lower eGFR was associated with increased p-cresol and indole biosynthetic potential and reduced plant-to-animal CAZyme ratios. This was consistent with community-wide saccharolytic-to-proteolytic microbiome transitions linked to dietary guidelines and slowed-down ITT. Peritoneal dialysis patients showed distinct microbiome dysbiosis accompanied by increased intestinal inflammation. Only Escherichia coli, an unnamed Alistipes species and Bifidobacterium adolescentis were covariate-independent markers for eGFR, but neither these nor previous microbial markers convincingly replicated across 11 studies. No predictors for CKD progression were found. Nevertheless, our study adds insight into plausible ITT and nutrition-related effects, highlighting their potential in CKD interventions.</p>","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125692","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 : 2026-02-03DOI: 10.1038/s41564-026-02275-w
{"title":"The building blocks of one of the most complex flagellar nanomachines.","authors":"","doi":"10.1038/s41564-026-02275-w","DOIUrl":"https://doi.org/10.1038/s41564-026-02275-w","url":null,"abstract":"","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113781","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 : 2026-02-02DOI: 10.1038/s41564-026-02263-0
Mariah Hassert, Lisa L. Drewry, Lecia L. Pewe, Lisa S. Hancox, Rui He, Sahaana Arumugam, Madison R. Mix, Aliasger K. Salem, John T. Harty
Immunization with radiation-attenuated sporozoites (RAS) drives effective sterilizing immunity against liver-stage Plasmodium infection. However, protection is compromised in individuals living in malaria endemic regions and the mechanisms of vaccine failure are unclear. Here we show that previous blood-stage exposure in a mouse model of Plasmodium yoelii infection compromises Plasmodium berghei RAS-induced essential CD8+ T cell responses and subsequent protection. The persisting malarial pigment haemozoin mediates impaired CD8+ T cell responses owing to impaired antigen uptake by dendritic cells, leading to reduced T cell activation. We designed a lipid nanoparticle-encapsulated mRNA vaccine that encodes a string of Plasmodium CD8+ T cell epitopes, which overcomes the defective T cell response and restores protection in Plasmodium-exposed mice. A combined RAS-plus-mRNA vaccine regimen enhances liver-resident memory T cells and protection in murine malaria-experienced hosts. The identification of haemozoin as a potential obstacle to vaccine efficacy in malaria endemic areas can inform the design of more effective malaria vaccines.
{"title":"mRNA vaccination overcomes haemozoin-mediated impairment of whole-parasite malaria vaccines in mice","authors":"Mariah Hassert, Lisa L. Drewry, Lecia L. Pewe, Lisa S. Hancox, Rui He, Sahaana Arumugam, Madison R. Mix, Aliasger K. Salem, John T. Harty","doi":"10.1038/s41564-026-02263-0","DOIUrl":"https://doi.org/10.1038/s41564-026-02263-0","url":null,"abstract":"Immunization with radiation-attenuated sporozoites (RAS) drives effective sterilizing immunity against liver-stage Plasmodium infection. However, protection is compromised in individuals living in malaria endemic regions and the mechanisms of vaccine failure are unclear. Here we show that previous blood-stage exposure in a mouse model of Plasmodium yoelii infection compromises Plasmodium berghei RAS-induced essential CD8+ T cell responses and subsequent protection. The persisting malarial pigment haemozoin mediates impaired CD8+ T cell responses owing to impaired antigen uptake by dendritic cells, leading to reduced T cell activation. We designed a lipid nanoparticle-encapsulated mRNA vaccine that encodes a string of Plasmodium CD8+ T cell epitopes, which overcomes the defective T cell response and restores protection in Plasmodium-exposed mice. A combined RAS-plus-mRNA vaccine regimen enhances liver-resident memory T cells and protection in murine malaria-experienced hosts. The identification of haemozoin as a potential obstacle to vaccine efficacy in malaria endemic areas can inform the design of more effective malaria vaccines.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"1 1","pages":""},"PeriodicalIF":28.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102121","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 : 2026-01-30DOI: 10.1038/s41564-025-02235-w
David Helekal, Tatum D. Mortimer, Aditi Mukherjee, Gabriella Gentile, Adriana Le Van, Sofia Blomqvist, Robert A. Nicholas, Ann E. Jerse, Samantha G. Palace, Yonatan H. Grad
The dynamics of antimicrobial resistance in bacterial populations are influenced by the fitness impact of genetic determinants of resistance and antibiotic pressure. However, estimates of real-world fitness impact have been lacking. To address this gap, we developed a hierarchical Bayesian phylodynamic model to quantify contributions of resistance determinants to strain success in a 20-year collection of Neisseria gonorrhoeae isolates. Fitness contributions varied with antibiotic use, which over this period included ciprofloxacin, cefixime, ceftriaxone and azithromycin, and genetic pathways to phenotypically identical resistance conferred distinct fitness effects. These findings were supported by competition experiments both in vitro and in the mouse model of gonococcal infection. Quantifying these fitness contributions to lineage dynamics reveals opportunities for investigation into other genetic and environmental drivers of fitness. This work thus establishes a method for linking pathogen genomics and antibiotic use to define factors shaping ecological trends. Phylodynamic modelling shows how the changing antibiotic landscape and genetic determinants of resistance shape real-world gonococcal dynamics. Experiments validated that determinants with identical resistance phenotype differed in impact on fitness.
{"title":"Quantifying the real-world impact of antibiotic use and genetic determinants of resistance on gonococcal dynamics","authors":"David Helekal, Tatum D. Mortimer, Aditi Mukherjee, Gabriella Gentile, Adriana Le Van, Sofia Blomqvist, Robert A. Nicholas, Ann E. Jerse, Samantha G. Palace, Yonatan H. Grad","doi":"10.1038/s41564-025-02235-w","DOIUrl":"10.1038/s41564-025-02235-w","url":null,"abstract":"The dynamics of antimicrobial resistance in bacterial populations are influenced by the fitness impact of genetic determinants of resistance and antibiotic pressure. However, estimates of real-world fitness impact have been lacking. To address this gap, we developed a hierarchical Bayesian phylodynamic model to quantify contributions of resistance determinants to strain success in a 20-year collection of Neisseria gonorrhoeae isolates. Fitness contributions varied with antibiotic use, which over this period included ciprofloxacin, cefixime, ceftriaxone and azithromycin, and genetic pathways to phenotypically identical resistance conferred distinct fitness effects. These findings were supported by competition experiments both in vitro and in the mouse model of gonococcal infection. Quantifying these fitness contributions to lineage dynamics reveals opportunities for investigation into other genetic and environmental drivers of fitness. This work thus establishes a method for linking pathogen genomics and antibiotic use to define factors shaping ecological trends. Phylodynamic modelling shows how the changing antibiotic landscape and genetic determinants of resistance shape real-world gonococcal dynamics. Experiments validated that determinants with identical resistance phenotype differed in impact on fitness.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 2","pages":"375-390"},"PeriodicalIF":19.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02235-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088951","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 : 2026-01-30DOI: 10.1038/s41564-025-02258-3
Brandon F Keele,Afam A Okoye,Taina T Immonen,Benjamin Varco-Merth,Derick Duell,Candice Nkoy,William Goodwin,Shelby Hoffmeister,Colette M Hughes,Emek Kose,Andrew Conchas,Charles A Goodman,Christine M Fennessey,Agatha Macairan,William J Bosche,Randy Fast,Christopher M Homick,Mike Hull,Kelli Oswald,Rebecca Shoemaker,Lorna Silipino,Jorden L Welker,Jeremy Smedley,Caralyn S Labriola,Michael K Axthelm,Scott G Hansen,Jacob D Estes,Dan H Barouch,Jeffrey D Lifson,Louis J Picker
The tissue origin(s) and the earliest viral dynamics of HIV rebound after antiretroviral therapy (ART) remain unclear. Here, using barcoded SIVmac239 in rhesus macaques (n = 24), we defined the distribution of barcode-specific viral RNA expression in tissues during ART (n = 6) and then assessed initial clonal rebound 5 and 7 days after ART cessation by identifying barcodes in individual tissues that exceeded the 99th percentile of the on-ART distribution ('outliers'). In 4 of 11 aviraemic and 6 of 7 viraemic animals, 32 such outlier barcodes were identified. Sixteen of these barcodes were also identified in rebound viraemia, confirming specific tissues as rebound origin and early amplification sites. Overall, 27 of the 32 outlier barcodes were determined to reflect rebound origins, of which 96% were in the gastrointestinal tract (26%) or gastrointestinal tract-associated lymphoid tissues (70%). These results indicate that distinct tissue sites differentially support post-ART viral rebound, with potential therapeutic implications for interventions designed to prevent or control these events.
{"title":"Initial sites of SIV rebound after antiretroviral treatment cessation in rhesus macaques.","authors":"Brandon F Keele,Afam A Okoye,Taina T Immonen,Benjamin Varco-Merth,Derick Duell,Candice Nkoy,William Goodwin,Shelby Hoffmeister,Colette M Hughes,Emek Kose,Andrew Conchas,Charles A Goodman,Christine M Fennessey,Agatha Macairan,William J Bosche,Randy Fast,Christopher M Homick,Mike Hull,Kelli Oswald,Rebecca Shoemaker,Lorna Silipino,Jorden L Welker,Jeremy Smedley,Caralyn S Labriola,Michael K Axthelm,Scott G Hansen,Jacob D Estes,Dan H Barouch,Jeffrey D Lifson,Louis J Picker","doi":"10.1038/s41564-025-02258-3","DOIUrl":"https://doi.org/10.1038/s41564-025-02258-3","url":null,"abstract":"The tissue origin(s) and the earliest viral dynamics of HIV rebound after antiretroviral therapy (ART) remain unclear. Here, using barcoded SIVmac239 in rhesus macaques (n = 24), we defined the distribution of barcode-specific viral RNA expression in tissues during ART (n = 6) and then assessed initial clonal rebound 5 and 7 days after ART cessation by identifying barcodes in individual tissues that exceeded the 99th percentile of the on-ART distribution ('outliers'). In 4 of 11 aviraemic and 6 of 7 viraemic animals, 32 such outlier barcodes were identified. Sixteen of these barcodes were also identified in rebound viraemia, confirming specific tissues as rebound origin and early amplification sites. Overall, 27 of the 32 outlier barcodes were determined to reflect rebound origins, of which 96% were in the gastrointestinal tract (26%) or gastrointestinal tract-associated lymphoid tissues (70%). These results indicate that distinct tissue sites differentially support post-ART viral rebound, with potential therapeutic implications for interventions designed to prevent or control these events.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"19 1","pages":""},"PeriodicalIF":28.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088953","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 : 2026-01-27DOI: 10.1038/s41564-025-02257-4
Yongtao Ye,Huiping Shuai,Yi Song,Marcus Ho-Hin Shum,David K Smith,Haogao Gu,Huachen Zhu,Joseph T Wu,Nicola S Lewis,Francesco Bonfante,Edward C Holmes,Malik Peiris,Leo Lit-Man Poon,Yi Guan,Tommy Tsan-Yuk Lam
Comparably few lineages of influenza A virus (IAV) have evolved long-term sustained transmission in mammals. The reasons remain largely unknown, and the possibility of avian IAVs evolving sustained mammalian transmission is an ongoing concern. Here we measured the GC content and frequency of GC dinucleotides in 115,520 whole genomes of IAVs using bioinformatic analyses. We found that persistent mammalian lineages showed declining trends in GC-related content and could be reliably separated from IAVs circulating only in birds and those sporadically infecting mammals. Similarly, the earliest viruses of persistent mammalian lineages showed reduced GC-related content, suggesting that this trait might in part contribute to their eventual persistence. Recent highly pathogenic 2.3.4.4b H5 viruses that spread in mink, foxes and humans were also characterized by reduced GC-related content. While not sufficient, reduced GC-related content may be a necessary condition for sustained mammalian transmission and should be included in risk assessment tools for pandemic influenza.
{"title":"Genomic features associated with sustained mammalian transmission of avian influenza A viruses.","authors":"Yongtao Ye,Huiping Shuai,Yi Song,Marcus Ho-Hin Shum,David K Smith,Haogao Gu,Huachen Zhu,Joseph T Wu,Nicola S Lewis,Francesco Bonfante,Edward C Holmes,Malik Peiris,Leo Lit-Man Poon,Yi Guan,Tommy Tsan-Yuk Lam","doi":"10.1038/s41564-025-02257-4","DOIUrl":"https://doi.org/10.1038/s41564-025-02257-4","url":null,"abstract":"Comparably few lineages of influenza A virus (IAV) have evolved long-term sustained transmission in mammals. The reasons remain largely unknown, and the possibility of avian IAVs evolving sustained mammalian transmission is an ongoing concern. Here we measured the GC content and frequency of GC dinucleotides in 115,520 whole genomes of IAVs using bioinformatic analyses. We found that persistent mammalian lineages showed declining trends in GC-related content and could be reliably separated from IAVs circulating only in birds and those sporadically infecting mammals. Similarly, the earliest viruses of persistent mammalian lineages showed reduced GC-related content, suggesting that this trait might in part contribute to their eventual persistence. Recent highly pathogenic 2.3.4.4b H5 viruses that spread in mink, foxes and humans were also characterized by reduced GC-related content. While not sufficient, reduced GC-related content may be a necessary condition for sustained mammalian transmission and should be included in risk assessment tools for pandemic influenza.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"105 1","pages":""},"PeriodicalIF":28.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056768","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 : 2026-01-27DOI: 10.1038/s41564-025-02213-2
Patrick O. Sorensen, Ulas Karaoz, Harry R. Beller, Markus Bill, Nicholas J. Bouskill, Jillian F. Banfied, Rosalie K. Chu, David W. Hoyt, Elizabeth Eder, Emiley Eloe-Fadrosh, Allison Sharrar, Malak M. Tfaily, Jason Toyoda, Nikola Tolic, Shi Wang, Allison R. Wong, Kenneth H. Williams, Yangquanwei Zhong, Eoin L. Brodie
Snowmelt triggers a soil microbial bloom and crash that affects nitrogen (N) export in high-elevation watersheds. The mechanisms underlying these microbial dynamics are uncertain, making soil nitrogen processes difficult to predict as snowpack declines globally. Here, integration of genome-resolved metagenomics, metatranscriptomics and metabolomics in a high-elevation watershed revealed ecologically distinct soil microorganisms linked across the snowmelt time-period by their unique nitrogen cycling capacities. The molecular properties and transformations of dissolved organic N suggested that degradation or recycling of microbial biomass provided N for biosynthesis during the microbial bloom. Winter-adapted Bradyrhizobia spp. oxidized amino acids anaerobically and had the highest gene expression for denitrification during the microbial bloom. A pulse of nitrate was driven by spring-adapted Nitrososphaerales after snowmelt, but dissimilatory nitrate reduction to ammonia (DNRA) gene expression indicated significant nitrate retention potential. These findings inform our understanding of nitrogen cycling in environments sensitive to snowpack decline due to global change. Soil microbial populations bloom and then die-off in ecosystems with seasonal snowpack. This study showed that distinct taxa utilize different N sources for growth or energy during the microbial bloom and alter the fate of N after snowmelt.
{"title":"Multi-omics reveals nitrogen dynamics associated with soil microbial blooms during snowmelt","authors":"Patrick O. Sorensen, Ulas Karaoz, Harry R. Beller, Markus Bill, Nicholas J. Bouskill, Jillian F. Banfied, Rosalie K. Chu, David W. Hoyt, Elizabeth Eder, Emiley Eloe-Fadrosh, Allison Sharrar, Malak M. Tfaily, Jason Toyoda, Nikola Tolic, Shi Wang, Allison R. Wong, Kenneth H. Williams, Yangquanwei Zhong, Eoin L. Brodie","doi":"10.1038/s41564-025-02213-2","DOIUrl":"10.1038/s41564-025-02213-2","url":null,"abstract":"Snowmelt triggers a soil microbial bloom and crash that affects nitrogen (N) export in high-elevation watersheds. The mechanisms underlying these microbial dynamics are uncertain, making soil nitrogen processes difficult to predict as snowpack declines globally. Here, integration of genome-resolved metagenomics, metatranscriptomics and metabolomics in a high-elevation watershed revealed ecologically distinct soil microorganisms linked across the snowmelt time-period by their unique nitrogen cycling capacities. The molecular properties and transformations of dissolved organic N suggested that degradation or recycling of microbial biomass provided N for biosynthesis during the microbial bloom. Winter-adapted Bradyrhizobia spp. oxidized amino acids anaerobically and had the highest gene expression for denitrification during the microbial bloom. A pulse of nitrate was driven by spring-adapted Nitrososphaerales after snowmelt, but dissimilatory nitrate reduction to ammonia (DNRA) gene expression indicated significant nitrate retention potential. These findings inform our understanding of nitrogen cycling in environments sensitive to snowpack decline due to global change. Soil microbial populations bloom and then die-off in ecosystems with seasonal snowpack. This study showed that distinct taxa utilize different N sources for growth or energy during the microbial bloom and alter the fate of N after snowmelt.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 2","pages":"359-374"},"PeriodicalIF":19.4,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02213-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056766","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 : 2026-01-27DOI: 10.1038/s41564-025-02238-7
Brendan Elsworth, Caroline D. Keroack, Yasaman Rezvani, Aditya S. Paul, Keare A. Barazorda, Niel C. Bauer, Jacob A. Tennessen, Samantha A. Sack, Cristina K. Moreira, Marc-Jan Gubbels, Marvin J. Meyers, Kourosh Zarringhalam, Manoj T. Duraisingh
Egress from host cells is fundamental for the spread of infection by apicomplexan parasites, including Babesia species. These tick-borne pathogens represent emerging zoonoses, but treatment options are limited. Here, using microscopy, transcriptomics and chemical genetics, we identified signalling, proteases and gliding motility as key drivers of egress by Babesia divergens. We developed reverse genetic tools in B. divergens to perform a knockdown screen of putative mediators of egress, identifying kinases and proteases involved in distinct steps of egress (aspartyl protease (ASP) 3 and kinases cGMP-dependent protein kinase (PKG) and calcium-dependent protein kinase (CDPK4)) and invasion (ASP2, ASP3 and PKG) of red blood cells. Inhibition of egress stimulates additional rounds of intracellular replication, indicating that exit from the replication cycle is uncoupled from egress. Chemical genetics validated PKG, CDPK4, ASP2 and ASP3 as druggable targets in Babesia spp. and identified promising compounds for babesiosis treatment. Taken together, egress in B. divergens more closely resembles egress in Toxoplasma gondii than in the more evolutionarily related Plasmodium spp. Analysis of Babesia divergens egress from host cells reveals druggable targets and identifies compounds for potential babesiosis treatment.
{"title":"Babesia divergens host cell egress is mediated by essential and druggable kinases and proteases","authors":"Brendan Elsworth, Caroline D. Keroack, Yasaman Rezvani, Aditya S. Paul, Keare A. Barazorda, Niel C. Bauer, Jacob A. Tennessen, Samantha A. Sack, Cristina K. Moreira, Marc-Jan Gubbels, Marvin J. Meyers, Kourosh Zarringhalam, Manoj T. Duraisingh","doi":"10.1038/s41564-025-02238-7","DOIUrl":"10.1038/s41564-025-02238-7","url":null,"abstract":"Egress from host cells is fundamental for the spread of infection by apicomplexan parasites, including Babesia species. These tick-borne pathogens represent emerging zoonoses, but treatment options are limited. Here, using microscopy, transcriptomics and chemical genetics, we identified signalling, proteases and gliding motility as key drivers of egress by Babesia divergens. We developed reverse genetic tools in B. divergens to perform a knockdown screen of putative mediators of egress, identifying kinases and proteases involved in distinct steps of egress (aspartyl protease (ASP) 3 and kinases cGMP-dependent protein kinase (PKG) and calcium-dependent protein kinase (CDPK4)) and invasion (ASP2, ASP3 and PKG) of red blood cells. Inhibition of egress stimulates additional rounds of intracellular replication, indicating that exit from the replication cycle is uncoupled from egress. Chemical genetics validated PKG, CDPK4, ASP2 and ASP3 as druggable targets in Babesia spp. and identified promising compounds for babesiosis treatment. Taken together, egress in B. divergens more closely resembles egress in Toxoplasma gondii than in the more evolutionarily related Plasmodium spp. Analysis of Babesia divergens egress from host cells reveals druggable targets and identifies compounds for potential babesiosis treatment.","PeriodicalId":18992,"journal":{"name":"Nature Microbiology","volume":"11 2","pages":"492-506"},"PeriodicalIF":19.4,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41564-025-02238-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056548","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 : 2026-01-26DOI: 10.1038/s41564-025-02241-y
Veronika Young, Bushra Dohai, Hridi Halder, Jaime Fernandez-Macgregor, Niels S. van Heusden, Thomas C. A. Hitch, Benjamin Weller, Patrick Hyden, Deeya Saha, Daan K. J. Pieren, Sonja Rittchen, Luke Lambourne, Sibusiso B. Maseko, Chung-Wen Lin, Ye Min Tun, Jonas Bibus, Luisa Pletschacher, Mégane Boujeant, Sébastien A. Choteau, Lou Bergogne, Jérémie Perrin, Franziska Ober, Patrick Schwehn, Simin T. Rothballer, Melina Altmann, Stefan Altmann, Alexandra Strobel, Michael Rothballer, Marie Tofaute, Daniel Kotlarz, Matthias Heinig, Thomas Clavel, Michael A. Calderwood, Marc Vidal, Jean-Claude Twizere, Renaud Vincentelli, Daniel Krappmann, Marianne Boes, Claudia Falter, Thomas Rattei, Christine Brun, Andreas Zanzoni, Pascal Falter-Braun
Pseudomonadota (formerly Proteobacteria) are prevalent in the commensal human gut microbiota, but also include many pathogens that rely on secretion systems to support pathogenicity by injecting proteins into host cells. Here we show that 80% of Pseudomonadota from healthy gut microbiomes also have intact type III secretion systems (T3SS). Candidate effectors predicted by machine learning display sequence and structural features that are distinct from those of pathogen effectors. Towards a systems-level functional understanding, we experimentally constructed a protein–protein meta-interactome map between human proteins and commensal effectors. Network analyses uncovered that effector-targeted neighbourhoods are enriched for genetic variation linked to microbiome-associated conditions, including autoimmune and metabolic diseases. Metagenomic analysis revealed effector enrichment in Crohn’s disease but depletion in ulcerative colitis. Functionally, commensal effectors can translocate into human cells and modulate NF-κB signalling and cytokine secretion in vitro. Our findings indicate that T3SS contribute to microorganism–host cohabitation and that effector–host protein interactions may represent an underappreciated route by which commensal gut microbiota influences health. Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.
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