PLoS Pathogens最新文献

{"title":"The devil in more detail: Eco-evolutionary genomics of Tasmanian devil persistence despite range-wide spread of a fatal, transmissible cancer.","authors":"Andrew Storfer, Marc A Beer, Dylan Gallinson, Menna E Jones, Rodrigo Hamede, Hamish McCallum, Mark J Margres","doi":"10.1371/journal.ppat.1013523","DOIUrl":"10.1371/journal.ppat.1013523","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013523"},"PeriodicalIF":4.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T6SS4 is heterogeneously expressed in Yersinia pseudotuberculosis and is a target for transcriptional and post-transcriptional regulation.","authors":"Anna Kerwien, Britta Körner, Ines Meyer, Yannick Teschke, Cassandra Sophie Köster, Ileana Paula Salto, Petra Dersch, Anne-Sophie Herbrüggen","doi":"10.1371/journal.ppat.1013356","DOIUrl":"10.1371/journal.ppat.1013356","url":null,"abstract":"<p><p>The type VI secretion system (T6SS) is a complex secretion system encoded by many Gram-negative bacteria to translocate effector proteins directly into target cells. Due to its high complexity and energy-intensive firing process, regulation of the T6SS is tightly controlled in many organisms. Y. pseudotuberculosis encodes four complete T6SS clusters but lacks genes implicated in T6SS gene regulation in other microorganisms, indicating a distinct control mechanism. Here, we could show that the T6SS4 of Y. pseudotuberculosis is heterogeneously expressed within a population, which is determined by the transcriptional T6SS4 activator RovC. Moreover, the T6SS4 and RovC are embedded in a complex and global regulatory network, including the global post-transcriptional regulator CsrA, the Yersinia modulator A (YmoA), the global protease Lon, and RNases (PNP and RNase III). Post-transcriptional processing of the T6SS4 polycistron and different transcript stability within the operon also achieve a higher regulatory complexity. In summary, our work provides new insights into the sophisticated and complex regulatory network of the T6SS4 of Y. pseudotuberculosis, which clearly differs from regulation in other organisms.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013356"},"PeriodicalIF":4.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring intracellular replication dynamics unveils high proportion of non-replicating antibiotic-tolerant Staphylococcus aureus inside osteoblasts.","authors":"Florian C Marro, Jacques Brocard, Allison Faure, Angélique Sion, Paul O Verhoeven, Laurie Canonne-Desbiolles, Laurence Conraux, Laura Jaffrelot, Chantal Monlong, Ariel J Blocker, Nelly Dubarry, Frédéric Laurent, Jérôme Josse","doi":"10.1371/journal.ppat.1013525","DOIUrl":"10.1371/journal.ppat.1013525","url":null,"abstract":"<p><p>Therapeutic failures and relapses are critical challenges in Staphylococcus aureus bone and joint infections. These issues may stem, in part, from the incomplete eradication of S. aureus residing within osteoblasts, the bone-forming cells, despite recommended antibiotic treatment. However, the mechanisms underlying intraosteoblastic S. aureus survival remain poorly understood. Here, we used automated real-time fluorescence microscopy at the single-host-cell level to monitor the intracellular replication dynamics of clinical S. aureus strains and their survivors of rifampicin treatment in MG-63 osteoblast cell line. S. aureus replication dynamics was heterogeneous both within and across strains, while survival to rifampicin treatment was uniformly characterized by a non-replicative phenotype. Surprisingly, rifampicin killed less than 0.3 log of intraosteoblastic S. aureus, and only during the early phase of infection. The majority of S. aureus that survived rifampicin treatment remained non-replicative intracellularly after rifampicin withdrawal, yet they retained the capacity to regrow on agar following release from host cells. This high proportion of non-replicative antibiotic-tolerant S. aureus inside osteoblasts may contribute to the high rates of therapeutic failures in bone and joint infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013525"},"PeriodicalIF":4.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum-anchored nonstructural proteins drive human astrovirus replication organelle formation.","authors":"Brooke Bengert, Samaneh Mehri, Madeline Holliday, Nicholas J Lennemann","doi":"10.1371/journal.ppat.1013538","DOIUrl":"10.1371/journal.ppat.1013538","url":null,"abstract":"<p><p>Human astroviruses (HAstV) are a major cause of acute, non-bacterial gastroenteritis and have been implicated in severe infections of the nervous system. Despite global prevalence, there are no established treatments for HAstVs due to a lack of understanding of the fundamental biology of infection, including mechanisms of viral replication. Like all positive-stranded RNA viruses, infection induces remodeling of host membranes into replication organelles (ROs). However, the intracellular membrane source and viral proteins involved in the coordination of HAstV ROs remain poorly defined. Using immunofluorescence microscopy, we determined that HAstV1 infection drives extensive restructuring of the endoplasmic reticulum (ER) to concentrate RNA replication and virus packaging. Long-term, time-lapse imaging of the ER and time point transmission electron microscopy (TEM) revealed that temporal manipulation of ER membrane corresponds with the emergence of ER-contiguous double membrane vesicles (DMV). The expression of transmembrane nonstructural proteins nsp1a/1, nsp1a/2, and nsp1a/1-2 led to the fragmentation of the ER for both HAstV1 and HAstV-VA1. However, only the expression of nsp1a/1-2 established DMV-like networks in the absence of an active infection. Further, super resolution microscopy revealed the organization of these two viral proteins in RO-like arrangements within the perinuclear region of infected cells. Together, these findings demonstrate the functions of nsp1a/1 and nsp1a/2 in the biogenesis of astrovirus-induced ROs, highlighting these proteins as exploitable targets for the design of antivirals restricting astrovirus replication.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013538"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The viral BCL2 protein BHRF1 of Epstein-Barr virus promotes AIM2 inflammasome activation to facilitate lytic replication.","authors":"Qingping Lan, Xiaolin Zhang, Yifan Sun, Jing Yang, Xiaojuan Li, Ersheng Kuang","doi":"10.1371/journal.ppat.1013509","DOIUrl":"10.1371/journal.ppat.1013509","url":null,"abstract":"<p><p>The absent in melanoma 2 (AIM2) protein recognizes viral and naked dsDNA and recruit apoptosis-associated speck-like protein containing CARD (ASC) to initiate inflammasome activation; however, the subversion of AIM2 activation by Epstein-Barr virus (EBV) infection remains unknown. Here, we reveal that the EBV-encoded viral BCL2 protein BHRF1 promotes AIM2 inflammasome activation. The BHRF1 C-terminal domain binds to AIM2 HIN domain and directly promotes dsDNA recognition and AIM2-ASC interaction, consequently cooperates with viral dsDNA to enable inflammasome activation. The single-site mutations R162A and F164A in BHRF1 and E186A in AIM2 abolish their interaction and AIM2 inflammasome activation. BHRF1 recruits AIM2 inflammasome to the mitochondrial compartment and facilitates EBV lytic replication through KAP1 and GSDMD cleavage. BHRF1 deficiency strongly decreases AIM2 inflammasome activation and EBV lytic replication, and reintroduction of wild-type BHRF1 but not the BHRF1 R162A or F164A mutant restores these functions. These results suggest that BHRF1 protein directly promotes the AIM2 inflammasome activation in the mitochondrial compartment to facilitate lytic replication.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013509"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interprotomer crosstalk in mosaic viral glycoprotein trimers provides insight into polyvalent immunogen co-assembly.","authors":"Chengbo Chen, Klaus N Lovendahl, Julie M Overbaugh, Kelly K Lee","doi":"10.1371/journal.ppat.1013143","DOIUrl":"10.1371/journal.ppat.1013143","url":null,"abstract":"<p><p>SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013143"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hepatitis E virus capsid protein ORF2 counteracts cell-intrinsic antiviral responses to enable persistent replication in cell culture.","authors":"Ann-Kathrin Mehnert, Sebastian Stegmaier, Carlos Ramirez Alvarez, Elif Toprak, Vladimir Gonçalves Magalhães, Carla Siebenkotten, Jungen Hu, Ana Luisa Costa, Daniel Kirrmaier, Michael Knop, Xianfang Wu, Thibault Tubiana, Carl Herrmann, Marco Binder, Viet Loan Dao Thi","doi":"10.1371/journal.ppat.1013516","DOIUrl":"10.1371/journal.ppat.1013516","url":null,"abstract":"<p><p>Hepatitis E virus (HEV) is a significant human pathogen causing both acute and chronic infections worldwide. The cell-intrinsic antiviral response serves as the initial defense against viruses and has been shown to be activated upon HEV infection. HEV can replicate in the presence of this response, but the underlying mechanisms remain poorly understood. Here, we investigated the roles of the structural proteins ORF2 and ORF3 in the cell-intrinsic antiviral response to HEV infection. Mechanistically, we validated that ectopic ORF2, but not ORF3, interfered with antiviral and inflammatory signaling downstream of pattern recognition receptors, in part through interaction with the central adaptor protein TANK binding kinase 1. In the full-length viral context, ORF2 contributed to a reduced antiviral response and consequently, more efficient viral replication. In addition, we discovered a protective mechanism mediated by ORF2 that shielded viral replication from antiviral effectors. Using single-cell RNA-sequencing, we confirmed that the presence of ORF2 in infected cells dampened antiviral responses in both actively infected cells and bystanders. As a consequence, we found that early in the infection process, the progression of authentic HEV infection relied on the presence of ORF2, facilitating a balance between viral replication and the antiviral response. Altogether, our findings shed new light on the multifaceted role of ORF2 in the HEV life cycle and improve our understanding of the determinants that contribute to persistent HEV replication in cell culture.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013516"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TisB enables antibiotic tolerance in Salmonella by preventing prophage induction through ATP depletion.","authors":"Sebastian Braetz, Niclas Nordholt, Andreas Nerlich, Frank Schreiber, Karsten Tedin, Marcus Fulde","doi":"10.1371/journal.ppat.1013498","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013498","url":null,"abstract":"<p><p>Persisters are phenotypically antibiotic-tolerant cells which can survive antibiotic exposure without acquiring antibiotic resistance. A proposed important factor in persistence is low intracellular ATP levels, which are thought to reduce the activity of antibiotic targets. However, previous studies demonstrated that persisters have comparable DNA damage as drug-sensitive bacteria after fluoroquinolone treatment. Furthermore, recent studies reported that endogenous prophages can reduce levels of antibiotic persistence in Salmonella after fluoroquinolone treatment. In this study, we examined prophage induction and persister cell survival of a prophage-free variant of Salmonella Typhimurium and strains harbouring a deletion of the tisAB genes, with tisB encoding the toxin from the tisB/istR-1 toxin-antitoxin system, known to reduce the intracellular ATP concentration. Treatment of the prophage-free variant with ciprofloxacin resulted in reduced killing and increased persistence as compared to the wild type. In addition, prophage induction and prophage mediated killing was significantly increased after deletion of tisAB following ciprofloxacin treatment. We also demonstrate that the recovery phase following the removal of ciprofloxacin, is crucial for the induction of endogenous prophages. Our results suggest that ATP-dependent prophage activation plays a significant role in DNA damage-mediated killing of bacteria. Low ATP levels can dampen the induction of prophages and increase the fraction of bacterial survivors after ciprofloxacin treatment.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013498"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The antifungal mechanism of EntV-derived peptides is associated with a reduction in extracellular vesicle release.","authors":"Giuseppe Buda De Cesare, Melissa R Cruz, Shane A Cristy, Luis A Vega, Robert Zarnowski, Antonino Zito, Shantanu Guha, David R Andes, Danielle A Garsin, Michael C Lorenz","doi":"10.1371/journal.ppat.1013519","DOIUrl":"10.1371/journal.ppat.1013519","url":null,"abstract":"<p><p>Candida albicans, an opportunistic fungal pathogen, causes systemic and superficial infections, especially in immunocompromised patients. Treatment of fungal infections is complicated by limited antifungal options and the development of drug resistance. Previous work from our group demonstrated the efficacy of the anti-virulence peptide EntV and shorter variants against C. albicans infection in various animal models, including mouse models of oropharyngeal candidiasis and disseminated infection and a rat venous catheter model. However, the mechanism of action, which abrogates fungal virulence without fungicidal or fungistatic activity, has remained unknown. We used a combination of cell biological, biochemical, genomic, and genetic approaches to identify this mechanism. We demonstrate that EntV-based peptides bind to the fungal cell envelope in a punctate and dynamic manner, co-localizing with extracellular vesicles (EVs), which play a critical role in fungal biofilm formation and virulence. Transcriptomic and genetic analyses further indicate that this activity is linked to the intracellular vesicular trafficking machinery, especially the ESCRT pathway, as mutations in this pathway alter sensitivity to EntV peptides and regulate virulence. We also show that EntV treatment significantly reduces EV secretion in C. albicans, supporting a novel mechanism of antifungal action through inhibition of EV-mediated virulence. These findings further develop EntV as a promising anti-virulence agent with potential for therapeutic development against drug-resistant fungal pathogens.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013519"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEPR2 perceives group II CEPs to regulate cell surface receptor-mediated immunity in Arabidopsis.","authors":"Jakub Rzemieniewski, Patricia Zecua-Ramirez, Sebastian Schade, Zeynep Camgöz, Genc Haljiti, Sukhmannpreet Kaur, Christina Ludwig, Ralph Hückelhoven, Martin Stegmann","doi":"10.1371/journal.ppat.1013115","DOIUrl":"10.1371/journal.ppat.1013115","url":null,"abstract":"<p><p>Plant endogenous peptides are crucial for diverse aspects of plant physiology. Among them, C-TERMINALLY ENCODED PEPTIDEs (CEPs) have recently emerged as important regulators of plant growth and stress responses. CEPs are divided into two major subgroups: group I CEPs and the less studied group II CEPs. We recently demonstrated that group I CEPs coordinate cell surface receptor-mediated immunity with nitrogen status in Arabidopsis thaliana (hereafter Arabidopsis). To mount full group I CEP responsiveness, the three phylogenetically related CEP RECEPTOR 1 (CEPR1), CEPR2 and RECEPTOR-LIKE KINASE 7 (RLK7) are required. Here, we provide evidence that biotic stress induces expression of the group II CEP peptide CEP14. CEP14 and the related CEP13 and CEP15 trigger hallmark immune signalling outputs in a proline hydroxylation pattern-dependent manner in Arabidopsis. Genetic data indicate that group II CEP members contribute to cell surface receptor-mediated immunity against bacterial infection. We further show that group II CEP perception primarily depends on CEPR2. Our work provides new insights into CEP function during biotic stress and sheds new light on the complexity of sequence-divergent CEP signalling mediated by specific endogenous receptors.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 9","pages":"e1013115"},"PeriodicalIF":4.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}