PLoS Pathogens最新文献

{"title":"BBK32 attenuates antibody-dependent complement-mediated killing of infectious Borreliella burgdorferi isolates.","authors":"Alexandra D Powell-Pierce, Charles E Booth, Payton G Smith, Brittany L Shapiro, Shannon S Allen, Brandon L Garcia, Jon T Skare","doi":"10.1371/journal.ppat.1013361","DOIUrl":"10.1371/journal.ppat.1013361","url":null,"abstract":"<p><p>Borreliella burgdorferi, the causative agent of Lyme disease, has evolved unique complement evasion proteins that promote its ability to establish and maintain infection in mammalian hosts. Among these is B. burgdorferi BBK32, a multifunctional surface lipoprotein that binds extracellular matrix (ECM) components, including fibronectin (Fn). In addition to its ECM-binding functions, BBK32 binds to C1r, the initiator protease of the classical pathway of complement, and protects B. burgdorferi from complement-mediated killing following exposure to normal human serum. The disparate functions of BBK32 in adhesion and complement evasion have previously been studied in isolation. Herein we demonstrate that full-length BBK32 binds both Fn and C1 concurrently, indicating that binding of these macromolecules do not sterically hinder their simultaneous interaction. Given the link of antibody dependence to the classical pathway, we tested how the presence of BBK32 would protect infectious B. burgdorferi from borrelial-specific antibodies in a complement-dependent manner. BBK32 provided protection against complement activation in the presence of borrelial-specific antibodies in vitro. We also demonstrated, using both flow cytometry and fluorescence microscopy, that BBK32 results in the reduction of C4 deposition on the surface of borrelial cells. This work demonstrates that BBK32 can simultaneously bind to both C1r and Fn and contributes to the broader understanding of the ability of B. burgdorferi to evade antibody-dependent complement-mediated killing. These observations are significant as they suggest that BBK32 plays a dual role in adhesion and dissemination in infectious B. burgdorferi, as well as immune evasion activities, which ostensibly promotes its pathogenic potential.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013361"},"PeriodicalIF":5.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709601","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":"A functional interleukin-4 homolog is encoded in the genome of infectious laryngotracheitis virus: Unveiling a novel virulence factor.","authors":"Jeremy D Volkening, Stephen J Spatz, Maricarmen Garcia, Teresa A Ross, Daniel A Maekawa, Kenneth S Rosenthal, Ana C Zamora, April Skipper, Julia R Blakey, Rashan Paudel","doi":"10.1371/journal.ppat.1013219","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013219","url":null,"abstract":"<p><p>Herpesviruses have evolved numerous immune evasion tactics, persisting within their hosts through self-perpetuating strategies. One such tactic involves acquiring functional copies of host genes encoding cytokines such as IL-6 (HHV-8), IL-10 (HHV-4, HHV-5), and IL-17 (SaHV-2). These viral mimics, or virokines, can bind to cellular receptors, modulating the natural cytokine signaling to manipulate the immune response in favor of the virus or stimulate target cell growth to enhance virus replication. In the course of full-length cDNA sequencing of infectious laryngotracheitis virus (ILTV) transcripts, a previously unknown highly spliced gene was discovered in the viral genome predicted to encode a 147 amino acid protein with similarity to vertebrate interleukin-4. The three-intron gene structure was precisely conserved with chicken and other vertebrate IL-4 homologs, and the amino acid sequence displayed structural conservation with vertebrate homologs at the primary, secondary, and tertiary levels based on computational modeling. The viral IL-4 gene was subsequently identified in all sequenced ILTV genomes. The mature transcript was highly expressed both in vitro and in vivo, and protein expression in infected cells was confirmed using LC-MS/MS. Phylogenetic analyses, along with the conserved gene structure, suggested direct capture from a Galliformes host. Functionally, an LPS-stimulation assay showed that the expressed viral IL-4 homolog stimulated nitric oxide production in a macrophage cell line at comparable levels to recombinant chicken IL-4. A recombinant virus lacking vIL-4 exhibited slightly higher titers in cell culture compared to the parental strain. In vivo bird studies demonstrated reduced pathogenicity of the vIL-4 knockout compared to wildtype. These results represent the first report of a previously unknown virokine encoded in the ILTV genome expressing a functional IL-4 homolog and virulence factor.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013219"},"PeriodicalIF":5.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700057","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":"Redefining the spliceosomal introns of the sexually transmitted parasite Trichomonas vaginalis and its close relative in columbid birds.","authors":"Francisco Callejas-Hernández, Mari Shiratori, Steven A Sullivan, Frances Blow, Jane M Carlton","doi":"10.1371/journal.ppat.1013282","DOIUrl":"10.1371/journal.ppat.1013282","url":null,"abstract":"<p><p>Trichomonas vaginalis infects the urogenital tract of men and women and causes the sexually transmitted infection trichomoniasis. Since the publication of its draft genome in 2007, the genome has drawn attention for several reasons, including its unusually large size, massive expansion of gene families, and high repeat content. The fragmented nature of the draft assembly made it challenging to obtain accurate metrics of features, such as spliceosomal introns. The number of introns identified has varied over the years, ranging from 41 when first characterized in 2005, to 32 in 2018 when the repertoire was revised. In both cases, the results suggested that more introns could be present in the genome. In this study, we exploited our new T. vaginalis G3 chromosome-scale assembly and annotation and high-coverage transcriptome datasets to provide an up-to-date repertoire of spliceosomal introns in the species. We developed a custom pipeline that distinguishes true splicing events from chimeric alignments by utilizing the extended motifs required by the splicing machinery, and experimentally verified the results using transcript evidence. We identified a total of 63 active introns and 34 putative \"inactive\" intron sequences in T. vaginalis, enabling an analysis of their length distribution, extended consensus motifs, intron phase distribution (including an unexpected expansion of UTR introns), and functional annotation. Notably, we found that a short intron in T. vaginalis, at only 23 nucleotides in size, is one of the shortest introns known to date. We tested our pipeline on a chromosome-scale assembly of the bird parasite Trichomonas stableri, the closest known relative to T. vaginalis. Our results revealed some conservation of the main features (total intron count, sequence, length distribution, and motifs) of these two closely related species, although differences in their functional annotation and duplication suggest alternative splicing machinery in T. vaginalis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013282"},"PeriodicalIF":4.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700174","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":"Lumpy skin disease virus 001/156 protein is a virulence factor that suppresses interferon production through impairing IRF3 dimerization.","authors":"Minmin Zhang, Yujie Shi, Xinyin Lu, Qiwei Zhang, Yubo Zhao, Shaohan Li, Zhiyuan Wen, Jinying Ge, Xijun Wang, Jie Li, Zhigao Bu, Xin Yin","doi":"10.1371/journal.ppat.1013362","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013362","url":null,"abstract":"<p><p>Lumpy skin disease virus (LSDV), a member of the genus Capripoxvirus within the family Poxviridae, causes significant disease in cattle and is classified as a notifiable disease by the World Organization for Animal Health (WOAH). The virus contains a double-stranded linear DNA genome of approximately 151 kbp, encoding 156 predicted open reading frames (ORFs) for various proteins. However, only a limited number of these proteins have been characterized, with the functions of many-particularly those encoded within the inverted terminal repeat (ITR) regions-remaining largely unknown. In this study, we utilized homologous recombination to generate LSDV mutants with deletions of the LSDV 001/156 gene to investigate its role. LSDV 001/156, an uncharacterized protein located within the ITR region, was identified as a late-expressed gene product incorporated into virions and involved in viral replication. Further analysis revealed that LSDV 001/156 acts as a negative regulator of the interferon (IFN) signaling pathway. It interacts with interferon regulatory factor 3 (IRF3), disrupting its dimerization and nuclear translocation, thereby attenuating IFN production. Functional studies demonstrated that the LSDV mutant lacking the 001/156 gene exhibited reduced replication and virulence in cattle compared to the wild-type virus, likely due to enhanced IFN responses in the absence of this immune-evasive protein. In summary, our findings uncover a novel role of the LSDV 001/156 gene in modulating the host intrinsic antiviral response, shedding light on the mechanisms underlying LSDV pathogenesis. This study highlights the importance of ITR-encoded genes in immune evasion and virulence, providing new insights into LSDV biology and its interactions with the host immune system.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013362"},"PeriodicalIF":5.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700058","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":"Through thick and thin: The vaginal microbiome as both occupant and healer.","authors":"Mart Sillen, Sarah Lebeer, Patrick Van Dijck","doi":"10.1371/journal.ppat.1013346","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013346","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013346"},"PeriodicalIF":5.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692096","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":"A chaperonin complex regulates organelle proteostasis in malaria parasites.","authors":"Amanda Tissawak, Yarden Rosin, Shirly Katz Galay, Alia Qasem, Michal Shahar, Nirit Trabelsi, Ora Furman-Schueler, Steven M Johnson, Anat Florentin","doi":"10.1371/journal.ppat.1013275","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013275","url":null,"abstract":"<p><p>The apicoplast of Plasmodium parasites serves as a metabolic hub that synthesize essential biomolecules. Like other endosymbiotic organelles, 90% of the apicoplast proteome is encoded by the cell nucleus and transported to the organelle. Evidence suggests that the apicoplast has minimal control over the synthesis of its proteome and therefore it is unclear how organelle proteostasis is regulated. Here, we identified and investigated a large and conserved chaperonin (CPN) complex with a previously unknown function. Using genetic tools, we demonstrated that ablation of the apicoplast CPN60 subunit leads to parasite death due to organellar damage, immediately within its first replication cycle, deviating from the delayed death phenotype commonly observed for apicoplast translation inhibitors. Unlike its close orthologues in other prokaryotic and eukaryotic cells, CPN60 is not upregulated during heat shock (HS) and does not affect HS response in the parasite. Instead, we found that it is directly involved in proteostasis through interaction with the Clp (caseinolytic protease) proteolytic complex. We showed that CPN60 physically binds both the active and inactive forms of the Clp complex, and manipulates its stability. A computational structural model of a possible interaction between these two large complexes suggests a stable interface. Finally, we screened a panel of inhibitors for the bacterial CPN60 orthologue GroEL, to test the potential of chaperonin inhibition as antimalarial. These inhibitors demonstrated an anti-Plasmodium activity that was not restricted to apicoplast function, with additional targets outside of this organelle. Taken together, this work reveals how balanced activities of proteolysis and refolding safeguard the apicoplast proteome, and are essential for organelle biogenesis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013275"},"PeriodicalIF":5.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692095","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":"Specific binding of human P[28] rotavirus VP8* protein to blood group ABH antigens on type 1 chains.","authors":"Yi Zheng, Xiaoman Sun, Yuting Li, Beibei Huang, Yang Chen, Han Zhou, Cuiyan Cao, Wengang Chai, Zhaojun Duan, Dandi Li, Jingyu Yan, Xinmiao Liang","doi":"10.1371/journal.ppat.1013298","DOIUrl":"10.1371/journal.ppat.1013298","url":null,"abstract":"<p><p>Group A rotavirus (RV) has been the major cause of acute gastroenteritis in infants and young children. Among the five P genogroups almost all P genotype RVs in P[II], P[III] and P[IV] genogroups that infect humans can bind glycan histo-blood group antigens (HBGAs) as the receptors on the host cell surface to infect host through the viral spike protein VP8*. Although P[I] is the largest genogroup, P[28] and P[10] are the only two genotype RVs infecting humans in the group. It has recently been found that a P[28] strain is related to bat RV and considered a possible product of reassortment between bat and human RVs. Bats are increasingly being recognized as an important reservoir for viruses crossing species barriers to infect humans. Unrevealing the interactions between RVs and host receptors is important for understanding RV evolution, infection, and epidemic. In the present study, using a multiphasic approach, including X-ray crystallography, glycan microarray with a dedicated probe library, bio-layer interferometry, site-specific mutagenesis, and molecular docking and dynamics simulations, we found that P[28]-VP8* can bind to all blood group A, B and H(O) antigens but on type 1 chain only, without the capability to bind to any Lewis epitopes or mucin O-glycan cores. Different from most of the prevalent human RVs, such as P[8], P[4] and P[6], the broad HBGA binding specificity of P[28]-VP8* and the fact of the recently identified a possible reassortment P[28] strain of bat and human RVs have raised the concern of a future possibility of P[I] genogroup RV epidemic. RV surveillance may also need to take the P[I] genogroup RVs into account in the future.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013298"},"PeriodicalIF":4.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683513","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":"Early-life RSV infection modulates innate immune events, preferentially enhancing allergen-induced type 2 lung inflammation in females.","authors":"Lydia Labrie, Rojine C McVea, Rami Karkout, Haya Aldossary, Véronique Gaudreault, Brian J Ward, Elizabeth D Fixman","doi":"10.1371/journal.ppat.1013340","DOIUrl":"https://doi.org/10.1371/journal.ppat.1013340","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) causes millions of hospitalizations and thousands of deaths per year globally. Early-life RSV infection is also associated with the subsequent development of wheezing and asthma, which exhibits sex-related disparities in incidence, epidemiology, and morbidity. The mechanisms that underlie these sex-specific effects are not clear. We have developed a combined infection-allergy model in which 10-day old mice are infected with RSV and subsequently exposed to a common allergen, house dust mite (HDM). We show that early-life exposure to RSV enhanced allergic lung inflammation upon HDM exposure 10 days after viral infection. Early-life RSV infection increased levels of the innate cytokine, IL-33, in the lung 6h following HDM exposure. Accumulation of CD11cmed eosinophils and group 2 innate lymphoid cells was more prominent in the lungs of female mice exposed to both RSV and HDM. Moreover, the numbers of IL-13+ T cells (both CD4+ and CD8+) in the lung were significantly increased in mice exposed to both RSV infection and HDM, although the expression of ST2 (the cognate receptor for IL-33) was not linked to T cell cytokine production. Inflammatory responses were maintained when the interval between RSV infection and HDM exposure was extended to one month. Thus, our results show that early exposure to RSV increased numbers of innate cells as well as T cells in response to a common allergen, whether delivered within days or after several weeks of viral infection and that most responses were enhanced in female mice. Our work highlights sex-specific impact of early-life viral infection on the developing lung, and suggests possible mechanisms to explain the subsequent predisposition to enhanced allergic responses long after viral clearance.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013340"},"PeriodicalIF":5.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683511","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":"Oligomerization of the Clostridioides difficile transferase B component proceeds through a stepwise mechanism.","authors":"Robin M Mullard, Michael J Sheedlo","doi":"10.1371/journal.ppat.1013186","DOIUrl":"10.1371/journal.ppat.1013186","url":null,"abstract":"<p><p>Clostridioides difficile is a gram-positive, pathogenic bacterium and is currently the leading cause of hospital-acquired, infectious diarrhea in the United States. During infection, C. difficile produces and secretes up to three toxins called Toxin A, Toxin B, and the C. difficile transferase (CDT). While Toxin A and Toxin B are thought to drive the pathology associated with the disease, strains that produce CDT have been linked to increased disease severity, higher rates of infection recurrence, and increased incidence of mortality. A basic understanding of how CDT intoxicates host cells has emerged over the past two decades and includes a framework that relies on the oligomerization of the components that comprise CDT to promote cellular intoxication. Although several key steps of this process have been biochemically described, a clear, molecular description of toxin assembly has not been resolved. We have collected cryogenic electron microscopy (Cryo-EM) data of purified, recombinant CDT. From these data, we have generated several structural snapshots of the toxin, including a series of structures that correspond to intermediates that form during oligomerization. These structures provide insight into the mechanism underlying toxin assembly and highlight a role for structural plasticity during this process. We have also shown that these partially assembled toxins are equally potent in cytotoxicity assays supporting this model in a cellular context. Finally, we show that CDTb oligomers are stabilized by CDTa and assembly is triggered by hydrophobic molecules.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013186"},"PeriodicalIF":4.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683512","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":"A highly potent human antibody neutralizing all serotypes of BK polyomavirus.","authors":"Marcel Weber, Simone Schmitt, Barbara Eicher, Jemima Seidenberg, Justina Rutkauskaite, Benedikt Stöckli, Catherine Townsend, Uyen Huynh-Do, Thomas Schachtner, Serena Delbue, Armin Mäder, Christoph Esslinger, Matthias Hillenbrand","doi":"10.1371/journal.ppat.1013122","DOIUrl":"10.1371/journal.ppat.1013122","url":null,"abstract":"<p><p>BK polyomavirus infection poses a significant risk to kidney transplant recipients. Reactivation of dormant virus in the transplanted kidney, triggered by immunosuppression, can lead to BK polyomavirus-associated nephropathy in up to 10% of transplants, often resulting in loss of graft function or even graft loss. Currently, there is no specific treatment that reliably prevents BK polyomavirus-associated nephropathy or halts its progression. Standard of care relies on reducing immunosuppression, allowing the immune system to gradually control the infection but at the risk of provoking rejection episodes and compromising kidney function. This study describes the discovery and characterization of a highly-potent BK polyomavirus-neutralizing antibody, identified from a kidney transplant recipient who displayed rapid clearance of high-level BKPyV-DNAemia. Antibody mAb 319C07 (USAN potravitug) neutralizes all four BK polyomavirus serotypes and recognizes an epitope critical for viral cell attachment. mAb 319C07 is in clinical development for the treatment of BKPyV infection in renal transplant patients (NCT05769582).</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 7","pages":"e1013122"},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664089","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}