Journal of Virology最新文献

{"title":"Endothelial cell-released mitochondrial DNA promotes B cell differentiation and virus replication during severe fever with thrombocytopenia syndrome virus infection.","authors":"Yun-Fa Zhang, Ning Cui, Tong Yang, Jin-Xia Wang, Jia-Hao Chen, Xin Yang, Yong-Xiang Wu, Li-Fen Hu, Xiao-Ai Zhang, Qing-Bin Lu, Xin Su, Hao Li, Wei Liu","doi":"10.1128/jvi.01323-24","DOIUrl":"10.1128/jvi.01323-24","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease acquired through tick bites. We have previously demonstrated the correlation between SFTSV-induced mitochondrial dysfunction and inflammation induction, disease progression, and fatal outcome. In the current study, our clinical observation study establishes a strong correlation between elevated levels of circulating cell-free mtDNA and poor prognosis. <i>In vivo</i> studies further reveal endothelial cells as an important source responsible for releasing mtDNA into circulation, which promotes B cell activation, migration, and differentiation via Toll-like receptor 9 (TLR9). Notably, TLR9 activation enhances B-cell susceptibility to SFTSV infection. These findings suggest that mtDNA released by injured endothelial cells facilitates B cell differentiation and virus replication, emphasizing the significant role of mitochondrial damage within endothelial cells in contributing to the severity of SFTS outcomes.IMPORTANCESevere fever with thrombocytopenia syndrome (SFTS) is a new acute tick-borne infectious disease with a high fatality rate of 10%-50%. There is a strong correlation between SFTSV-induced mitochondrial dysfunction and inflammation induction, disease progression, and fatal outcome. Our research has revealed the crucial role of mtDNA in predicting the prognosis of SFTS and its impact on vascular endothelial injuries as well as B cell differentiation, two previously unexplored features of SFTSV infection. Moreover, mtDNA could activate the TLR9 signal to induce plasmablast differentiation in B cells and promote SFTSV infection. This study provides valuable mechanistic and clinical insights into the adverse outcomes associated with SFTSV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0132324"},"PeriodicalIF":4.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The A487 residue in the E protein of duck Tembusu virus significantly enhances viral replication and increases its neurovirulence in Kunming mice.","authors":"Yu He, Jiaqi Guo, Xiaoli Wang, Zhen Wu, Tao Wang, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Qiao Yang, Ying Wu, Shaqiu Zhang, Juan Huang, Xumin Ou, Di Sun, Anchun Cheng, Shun Chen","doi":"10.1128/jvi.00308-25","DOIUrl":"10.1128/jvi.00308-25","url":null,"abstract":"<p><p>Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe egg-drop syndrome and encephalitis in ducks. Although ducks are the natural host, mice serve as a valuable model for studying neuropathogenesis, as TMUV-infected mice recapitulate key neurological symptoms observed in ducks, such as paralysis and encephalitis. In the previous study, we observed that the TMUV strain CQW1 exhibited unexpectedly low neurovirulence in mice compared with earlier strains, highlighting potential genetic determinants of pathogenicity that may influence viral evolution and disease outcomes in natural hosts. In this study, we investigated the murine neurovirulence of TMUV strains from two major phylogenetic clusters (2.1 and 2.2). The Cluster 2.2 strain CHN-YC demonstrated markedly higher neurovirulence in Kunming mice than Cluster 2.1 strains (CQW1 and SCS01), with robust viral replication in the brain, pronounced histopathological damage, and elevated proinflammatory cytokine levels. Comparative genomic analysis identified seven amino acid substitutions in the E-NS1 region, with variations unique to Cluster 2.1 strains or specific to CQW1. By introducing these substitutions into CQW1 via reverse genetics, we restored high murine neurovirulence and identified the E protein substitution V487A as critical for this phenotype. Mechanistically, E-V487A enhances viral assembly, which boosts replication efficiency <i>in vitro</i> and <i>in vivo</i>. This substitution is located in the E protein transmembrane domain, a region implicated in flavivirus particle formation. Our data revealed that a naturally occurring amino acid substitution located in the transmembrane domain of the Tembusu virus E protein is responsible for its high neurovirulence in mice.</p><p><strong>Importance: </strong>Tembusu virus is a mosquito-borne avian orthoflavivirus, exhibiting airborne transmission. Although it primarily affects domestic fowl, TMUV demonstrates high neurovirulence in mice during laboratory studies and has been reported to spill over into humans. Recent years have seen increased genetic diversity and an expanded host range of the virus. Strains belonging to phylogenetic cluster 3 can cause severe neurological symptoms and death in mice via intranasal infection, further highlighting its risk of potential transmission to mammals. Understanding their pathogenicity and the underlying molecular basis is crucial for assessing and preventing health risks to mammals. We identified a single amino acid substitution in the TMUV E protein that critically enhances viral replication and neurovirulence in mice. The data provide insights into the molecular mechanisms of Tembusu virus pathogenesis in mammals and underscore the impact of specific genetic mutations on the viral phenotype.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0030825"},"PeriodicalIF":4.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening bacterial effectors and human virus proteins in yeast to identify host factors driving tombusvirus RNA recombination: a role for autophagy and membrane phospholipid content.","authors":"Judit Pogany, Jun-Ichi Inaba, Yuyan Liu, Peter D Nagy","doi":"10.1128/jvi.01661-24","DOIUrl":"10.1128/jvi.01661-24","url":null,"abstract":"<p><p>Recombination in RNA viruses contributes to virus evolution and rapid emergence of new viral variants that helps evade host's antiviral strategies. Host factors play important but poorly characterized roles in viral RNA recombination. The authors expressed <i>Legionella</i> bacterium effector proteins and SARS-CoV-2 and human metapneumovirus (HMPV) proteins in yeast to test their effects on tomato bushy stunt virus (TBSV) RNA recombination. The identified 16 <i>Legionella</i> effectors, six SARS-CoV-2, and two HMPV proteins affecting TBSV recombination likely target shared host factors with TBSV. Among the targets of the effectors/viral proteins was the autophagy pathway. Inhibition of autophagy by expression of RavZ and LegA9 <i>Legionella</i> effectors reduced the production of TBSV recombinants in yeast and plants. Induction of autophagy by rapamycin, via nitrogen starvation of yeast or overexpression of ATG2 lipid transfer protein, led to enhanced viral RNA recombination. Using <i>in vitro</i> TBSV replicase assembly on giant unilamellar vesicles confirmed the critical role of phosphatidylethanolamine in RNA recombination. We suggest that the pro-recombination role of co-opted autophagy is to provide abundant phospholipids for viral replication organelle biogenesis. Overall, this work highlights the critical roles of membrane phospholipids and lipid context in the regulation of viral RNA recombination. We show that SARS-CoV-2 N and HMPV M2-1 proteins enhance TBSV RNA replication and recombination by protecting the viral RNAs from host Xrn1 5´-3´ exoribonuclease in yeast. Altogether, the novel strategy of using TBSV as a cellular system sensor might assist in the identification of novel functional targets of various viral and bacterial effectors in yeast.</p><p><strong>Importance: </strong>Positive-strand (+)RNA viruses replicate in the cytosol of infected cells by exploiting cellular proteins and resources that frequently lead to diseases. Virus replication results in the generation of viral RNA recombinants that contribute to the emergence of new viral variants and adaptation to new hosts. The authors expressed <i>Legionella</i> bacterium effector proteins, SARS-CoV-2 and human metapneumovirus proteins in yeast to test their effects on tomato bushy stunt virus (TBSV) RNA recombination. This novel approach revealed that <i>Legionella</i> effectors and heterologous viral proteins target shared host factors with TBSV, including the autophagy pathway. <i>In vitro</i> approach revealed that the pro-recombination role of co-opted autophagy is to provide abundant phospholipids for viral replication. SARS-CoV-2 nucleocapsid protein and human metapneumovirus M2-1 protein are shown to enhance TBSV RNA replication and recombination by protecting the viral RNAs from host Xrn1 5´-3´ exoribonuclease in yeast. Thus, the TBSV/yeast system can be used as a cellular system sensor to find new functions of heterologous viral proteins.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0166124"},"PeriodicalIF":4.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hnRNPM regulates influenza A virus replication through distinct mechanisms in human and avian cells: implications for cross-species transmission.","authors":"Qin Zhang, Lei Zhang, Jinghua Li, Wenyu Zhang, Jianwei Wang, Tao Deng","doi":"10.1128/jvi.00067-25","DOIUrl":"10.1128/jvi.00067-25","url":null,"abstract":"<p><p>The eight-segmented RNA genome of influenza A virus (IAV) is transcribed and spliced into 10 major viral mRNAs in the nucleus of infected cells. Both transcription and splicing are facilitated by the host RNA polymerase II (Pol II) machinery via interactions between the viral ribonucleoprotein (vRNP) complex and various host factors. In this study, we demonstrate that IAV vRNPs recruit species-specific heterogeneous nuclear ribonucleoprotein M (hnRNPM) to support their replication in human and avian cells through distinct mechanisms. In A549 cells, human hnRNPM specifically facilitates the efficient transcription of HA, NA, M, and NS segments of WSN virus in a gene coding sequence-dependent manner. In contrast, in DF-1 cells, chicken hnRNPM restricts excessive splicing of M segment mRNA to ensure proper M2 protein production. Notably, human hnRNPM, with 34 additional amino acids compared with its chicken counterpart, fails to inhibit the M2 expression in DF-1 cells, whereas both human and chicken hnRNPM regulate WSN virus replication similarly in A549 cells. These findings highlight the host-specific roles of M2 levels in IAV replication and reveal how IAV co-opts host factors through virus genome sequence-dependent and host species-specific mechanisms, underscoring its high flexibility and adaptability during cross-species transmission.IMPORTANCEThe transcription and splicing of IAV genome in the nucleus of infected cells are precisely regulated to produce optimal amounts of viral proteins, ensuring efficient virus replication. In this study, we discovered that human hnRNPM regulates the IAV segment-specific differential transcription in a coding sequence-dependent manner in human cells. In contrast, chicken hnRNPM specifically inhibits M2 mRNA splicing to maintain proper M2 protein levels in avian cells. These species-specific regulatory mechanisms highlight the distinct replication strategies employed by IAV in human versus avian cells and underscore the complexity of cross-species transmission.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0006725"},"PeriodicalIF":4.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naturally transmitted mouse viruses highlight the heterogeneity of virus transmission dynamics in the dirty mouse model.","authors":"Dira S Putri, Frances K Shepherd, Autumn E Sanders, Shanley N Roach, Sridevi Jay, Mark J Pierson, Garritt Wieking, Jodi L Anderson, David K Meyerholz, Timothy W Schacker, Ryan A Langlois","doi":"10.1128/jvi.00187-25","DOIUrl":"10.1128/jvi.00187-25","url":null,"abstract":"<p><p>Specific-pathogen-free (SPF) mice are widely used in biomedical research to model human infections. However, these animals do not always accurately recapitulate human immune responses. This is due, in part, to their lack of infection history. A growing number of studies show that the host microbiome influences the development, progression, and responses of many diseases. To date, the majority of research on the microbiome has focused on the bacterial populations and less on the eukaryotic virome of the host. Here, we characterize a transmission model where SPF mice are exposed to natural mouse pathogens at physiologic doses and routes. We found that pet store mice acquired from different sources have distinct viromes and infection histories. We also found significant heterogeneity in the kinetics of the transmission of natural mouse viruses. A common virus found in our model was murine Kobuvirus. Surprisingly, murine Kobuvirus infection was found in the glandular stomach epithelia and not intestinal epithelia like other enteric picornaviruses. Together, these data characterize the heterogeneity of the dirty mouse cohousing system and provide a foundation for studying the biology of natural mouse viruses.</p><p><strong>Importance: </strong>Increasing evidence supports microbial exposure as a critical factor in shaping responses to immune challenges such as infections and vaccinations. However, many experimental models introducing microbial exposure into laboratory animals have confounding factors that may impact phenotypes and are not well characterized. Here, we characterized the pet store reservoir virome diversity, prior infection history, and transmission kinetics. We found significant heterogeneity across these features of the pet store cohousing model. Moreover, we leveraged this model to investigate the tropism of two less characterized viruses-murine Kobuvirus and murine astrovirus 2-in a natural transmission setting. These findings highlight the importance of characterizing the virome of pet store reservoirs to better mimic microbial exposure in humans.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0018725"},"PeriodicalIF":4.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mimivirus transcription and translation occur at well-defined locations within amoeba host cells.","authors":"Lotte Mayer, Georgi Nikolov, Martin Kunert, Matthias Horn, Anouk Willemsen","doi":"10.1128/jvi.00554-25","DOIUrl":"https://doi.org/10.1128/jvi.00554-25","url":null,"abstract":"<p><p>Many giant viruses replicate in the cytoplasm in viral factories. How exactly these viral factories are established and where the different steps of the replication cycle occur remain largely obscure. We have developed a single-molecule messenger RNA fluorescence <i>in situ</i> hybridization (smFISH) protocol for giant viruses in an <i>Acanthamoeba</i> host. Combined with other labeling techniques (FUNCAT, DiD, rRNA FISH, and DAPI), we show the Mimivirus transcription and translation sites during an infection cycle in the amoeba host cell. Although viral mRNA localization changes depend on the infection stage, transcription occurs at well-defined spots within the viral factory. The original viral cores released within the cytoplasm most likely define these spots. When transported outside of the viral factory, the translation of viral mRNA takes place in a well-defined ring surrounding it. With this study, we obtained novel insights into giant virus replication, of which the methods are widely applicable to other viruses for the visualization and quantification of RNA molecules.IMPORTANCEGiant viruses have massive particle and genome sizes, which are known to infect unicellular eukaryotes. Although most viruses replicate in the host cell's nucleus, the giant Mimivirus replicates in viral factories established in the host cell's cytoplasm. Before this study, the location of the various steps in the Mimivirus replication cycle was largely unknown. By developing new protocols to label giant virus mRNA, protein synthesis, host cell membranes and rRNA, we demonstrate that Mimivirus transcription occurs at well-defined sites within the viral factory. In contrast, translation takes place directly outside of it. This is different from other viruses known to have a cytoplasmic life cycle. These results bring us a step closer to understanding how the genome complexity of viruses influences the virus-host interactions and viral replication strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0055425"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host origin is a determinant of coevolution between gene segments of avian H9 influenza viruses.","authors":"Jennifer E Jones, Seema S Lakdawala","doi":"10.1128/jvi.01518-24","DOIUrl":"https://doi.org/10.1128/jvi.01518-24","url":null,"abstract":"<p><p>Several emerging influenza viruses, including H7N9 and H5N6 viruses, trace their origins to reassortment with H9N2 viruses that contributed internal gene segments. However, the evolutionary constraints governing the reassortment of H9N2 viruses remain unknown. In seasonal human influenza A viruses, gene segments coevolve at both the nucleotide and amino acid levels. Here, we demonstrate that evolutionary relationships between gene segments, including polymerase subunits in human H3N2 viruses, differ from avian H9 viruses. Avian H9 viruses were characterized by little coevolution between gene segments or between polymerase subunits. Strikingly, protein trees built from avian H9 polymerase subunits diverge despite known functional constraints on polymerase evolution. The evolutionary divergence observed between gene segments of avian H9 viruses was consistent across isolates from different continents, suggesting that coevolution between H9 gene segments is not dependent on regionally defined avian lineages. Instead, coevolution between gene segments was only found in H9 viruses that crossed the species barrier into humans. Our study reveals the role of the host in the coevolution of influenza gene segments and suggests that high reassortment potential in avian species may be a consequence of evolutionary flexibility between gene segments.IMPORTANCEEmerging pandemic influenza viruses can contain a combination of viral gene segments from avian, swine, and/or human species through the process of reassortment. H9 viruses have been important gene segment donors to several avian viruses of concern, including H5N1 and H7N9. In this work, we found that H9 gene segments and proteins do not have constrained evolutionary relationships typical of human seasonal influenza viruses, suggesting a flexibility that could allow for greater reassortment potential. However, we also found that this observation was dependent upon the host species source, with greater evolutionary constraints in H9 viruses from human sources. Understanding such constraints that underlie viral reassortment is critical to predicting future viruses that may be feasible in nature and have pandemic potential.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0151824"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of SARS-CoV-2 RBD immunogens to focus immune responses toward conserved coronavirus epitopes.","authors":"Caitlin Harris, A Brenda Kapingidza, James E San, Jayani Christopher, Tyler Gavitt, Brianna Rhodes, Katarzyna Janowska, Christopher O'Donnell, Jared Lindenberger, Xiao Huang, Salam Sammour, Madison Berry, Maggie Barr, Rob Parks, Amanda Newman, Mary Overton, Thomas Oguin, Priyamvada Acharya, Barton F Haynes, Kevin O Saunders, Kevin Wiehe, Mihai L Azoitei","doi":"10.1128/jvi.00465-25","DOIUrl":"10.1128/jvi.00465-25","url":null,"abstract":"<p><p>SARS-CoV-2 continues to evolve, with new variants emerging that evade pre-existing immunity and limit the efficacy of existing vaccines. One approach toward developing superior, variant-proof vaccines is to engineer immunogens that preferentially elicit antibodies with broad cross-reactivity against SARS-CoV-2 and its variants by targeting conserved epitopes on spike. The inner and outer faces of the receptor binding domain (RBD) are two such conserved regions targeted by antibodies that recognize diverse human and animal coronaviruses. To promote the elicitation of such antibodies by vaccination, we engineered \"resurfaced\" RBD immunogens that contained mutations at exposed RBD residues outside the target epitopes. In the context of pre-existing immunity, these vaccine candidates aim to disfavor the elicitation of strain-specific antibodies against the immunodominant receptor binding motif (RBM) while boosting the induction of inner and outer face antibodies. The engineered resurfaced RBD immunogens were stable, lacked binding to monoclonal antibodies with limited breadth, and maintained strong interactions with target broadly neutralizing antibodies. When used as vaccines, they limited humoral responses against the RBM as intended. Multimerization on nanoparticles further increased the immunogenicity of the resurfaced RBD immunogens, thus supporting resurfacing as a promising immunogen design approach to rationally shift natural immune responses to develop more protective vaccines.IMPORTANCESARS-CoV-2 is the third coronavirus to cause significant human disease over the last two decades. Despite their success in preventing serious disease, current SARS-CoV-2 vaccines must be updated regularly to match the circulating strains for continued protection. Therefore, it would be advantageous to develop vaccines that protect more broadly against SARS-CoV-2, its variants, and other pre-emergent coronaviruses. This may be achieved by preferentially eliciting antibodies against conserved regions of the spike protein that decorates the virus. Toward this goal, we engineered vaccine candidates to target the conserved inner and outer domains of the Receptor Binding Domain of SARS-CoV-2, by altering the surface of the wild-type protein such that strain-specific antibodies that bind outside these regions are no longer recognized. When used in animals with pre-existing SARS-CoV-2 immunity, these molecules reduce the elicitation of variant-specific antibodies, thus providing a blueprint to alter the natural immunodominance hierarchies of SARS-CoV-2 proteins.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0046525"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MARCH6 suppresses Tembusu virus replication by targeting viral NS5 protein for TOLLIP-mediated selective autophagic degradation.","authors":"Peng Zhou, Wanrong Wu, Jiani Wei, Yueshan Yang, Anan Jongkaewwattana, Yuncai Xiao, Hui Jin, Hongbo Zhou, Rui Luo","doi":"10.1128/jvi.00735-25","DOIUrl":"https://doi.org/10.1128/jvi.00735-25","url":null,"abstract":"<p><p>The E3 ligase membrane-associated RING finger 6 (MARCH6) plays a pivotal role in various cellular processes; however, its role in viral defense remains largely unexplored. In this study, we have elucidated a novel antiviral mechanism of avian MARCH6 against duck Tembusu virus (TMUV), revealing a previously uncharacterized host defense strategy. Notably, MARCH6 expression was significantly upregulated during TMUV infection in several duck cell lines, suggesting a conserved cellular response. Functional analyses revealed that overexpression of MARCH6 effectively suppressed TMUV replication, whereas its knockdown markedly enhanced viral replication. Mechanistically, MARCH6 directly interacts with the viral non-structural protein 5 (NS5), mediating its targeted degradation through an unprecedented E3 ligase activity-independent mechanism. Moreover, MARCH6 recruits the autophagic cargo receptor TOLLIP, which facilitates the NS5-TOLLIP interaction independent of ubiquitin signaling and subsequently directs NS5 to phagophores for degradation. These findings reveal a novel antiviral mechanism that focuses on the MARCH6-NS5-TOLLIP axis and represents a critical host defense strategy against viral infections. This study not only provides insights into the antiviral functions of MARCH6 but also emphasizes the importance of selective autophagy as a fundamental mechanism to control viral infection.IMPORTANCETMUV, an emerging pathogenic flavivirus, has rapidly spread across major duck farming regions in Asia since 2010, causing substantial economic losses in the duck industry. More recently, TMUV has expanded its host range, raising concerns about its potential threat to mammals. Understanding TMUV-host interactions is essential for developing effective treatments and vaccines. Here, we uncover a previously uncharacterized role of avian MARCH6 in antiviral defense against TMUV. We demonstrate that MARCH6 restricts TMUV replication through an E3 ligase activity-independent mechanism by targeting the viral NS5 protein for degradation. Notably, MARCH6 promotes NS5 degradation via selective autophagy by recruiting the cargo receptor TOLLIP, bypassing conventional ubiquitin signaling. These findings reveal a novel host antiviral strategy centered on the MARCH6-NS5-TOLLIP axis, broadening our understanding of selective autophagy in antiviral defense.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0073525"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSDMD and GSDME exhibit distinct roles in enteric coronavirus PDCoV-induced pyroptosis and inflammatory responses.","authors":"Chenyu Li, Yuting Shi, Chunying Xie, Kaiqi Duan, Tong Ding, Xiangfei Xu, Liurong Fang, Yanrong Zhou, Shaobo Xiao","doi":"10.1128/jvi.01876-24","DOIUrl":"https://doi.org/10.1128/jvi.01876-24","url":null,"abstract":"<p><p>Porcine deltacoronavirus (PDCoV), an emerging enteric coronavirus with zoonotic potential, typically causes intestinal villous epithelial cell damage with inflammation. Pyroptosis is a recently identified inflammatory form of programmed cell death that has been found to be associated with the pathogenesis of many viruses. However, the effects of PDCoV infection on pyroptosis and the role of pyroptosis in its pathogenesis remain unclear. In this study, we report that PDCoV infection triggers pyroptosis, as demonstrated in porcine ileum epithelial cell lines and intestinal tissues of PDCoV-infected piglets. Although both gasdermin D (GSDMD)- and gasdermin E (GSDME)-mediated pyroptosis were observed during PDCoV infection, GSDME dominated PDCoV-induced pyroptosis and subsequent inflammatory responses. More differently, GSDMD, rather than GSDME, exhibited potent anti-PDCoV activity; however, PDCoV-encoded nonstructural protein 5, a 3C-like protease, cleaved GSDMD, but not GSDME, to abolish the antiviral and pyroptotic functions of GSDMD. Our study elucidates the distinct roles of GSDMD and GSDME in PDCoV-induced pyroptosis and inflammatory responses, providing new insight into the pathogenesis of PDCoV and the potential for anti-PDCoV drug development.IMPORTANCEPyroptosis is a type of programmed cell death mediated by various gasdermins (GSDMs). While previous research has primarily focused on the role of GSDMD in pyroptosis, our study demonstrates that GSDME plays a dominant role in pyroptosis and the concomitant inflammatory responses induced by porcine deltacoronavirus (PDCoV), a newly identified enteric coronavirus with the potential to infect humans. The cleavage of GSDMD by PDCoV 3C-like protease may account for the diminished functionality of GSDMD in PDCoV-induced pyroptosis, which simultaneously disrupts its antiviral potential against PDCoV. These findings reveal the intricate interplay between PDCoV, GSDMD, and GSDME, accelerating the elucidation of PDCoV pathogenicity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0187624"},"PeriodicalIF":4.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}