Journal of Virology最新文献

{"title":"Development of DNA and mRNA-LNP vaccines against an H5N1 clade 2.3.4.4b influenza virus.","authors":"Rebecca A Leonard, M Ariel Spurrier, Samantha Skavicus, Zhaochen Luo, Brook E Heaton, Rachel L Spreng, Jiaqi Hong, Fan Yuan, Nicholas S Heaton","doi":"10.1128/jvi.00795-25","DOIUrl":"https://doi.org/10.1128/jvi.00795-25","url":null,"abstract":"<p><p>Effective vaccines are an important public health tool which may be needed to combat the emerging, highly pathogenic H5N1 avian influenza viruses currently circulating in cattle and poultry in the United States. While nucleic acid-based vaccines such as mRNA-lipid nanoparticles (LNPs) have several potential advantages during a viral epidemic compared to traditional seasonal influenza vaccines, their utility and efficacy against H5N1 viruses remain incompletely defined. Here, we developed novel DNA- and mRNA-LNP-based vaccines encoding both hemagglutinin (HA) and neuraminidase (NA) proteins from the human-isolated highly pathogenic avian influenza H5N1 strain, A/Texas/37/2024, in a single open reading frame. This dual-antigen expression approach elicited strong protective immune responses targeting both the HA and NA proteins and provided complete protection against lethal viral challenges in a murine model. The pre-clinical data described in this work suggest that these multi-valent, adaptable, and scalable vaccine approaches may represent practical and rapid solutions to mediate robust protection from emerging zoonotic influenza virus threats.</p><p><strong>Importance: </strong>Vaccines capable of protecting from infection with the H5N1 influenza viruses actively circulating in dairy cattle could be deployed to protect livestock and potentially also be used to protect human health. Here, we describe the development of protective DNA and mRNA-lipid nanoparticle vaccines targeting hemagglutinin and neuraminidase proteins from the highly pathogenic avian influenza (HPAI) H5N1 A/Texas/37/2024 virus and show that they are both protective against severe morbidity and mortality in a mouse model. Thus, the vaccines described in this work represent effective approaches to limit the current circulation of H5N1 viruses in animals and may represent practical solutions for human vaccination in the event of sustained human transmission of HPAI H5N1 viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0079525"},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642888","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":"A novel aptamer-based dNTP assay reveals that intact HIV virions are highly stable and do not contain enough dNTPs to support DNA synthesis.","authors":"Urja Biswas, Cynthia Bernal, Ruofan Wang, Jeffrey J DeStefano","doi":"10.1128/jvi.00564-25","DOIUrl":"10.1128/jvi.00564-25","url":null,"abstract":"<p><p>HIV virions contain high concentrations of IP6 (inositol hexakisphosphate), which stabilize capsids by binding to pores that allow dNTPs to import into capsids during infection. The concentration of dNTPs in virions, however, is not known. The low cellular concentrations (~5 µM each) predict only ~1 copy of each dNTP in a virion, unless a mechanism for concentrating exists, as it does for IP6. Reports indicating significant DNA synthesis occurring in virions would require larger amounts of packaged dNTPs or import of dNTPs. We developed a novel aptamer-based assay capable of detecting 1 femtomole of dNTP, enabling dNTP measurements in virions. Virions from HEK 293T cells contained dNTPs with dTTP >dCTP ≈ dATP >dGTP. This order was also observed in uninfected cells. Concentrations of dNTPs in virions were 2-fold to 4-fold lower than in cells, although it was unclear if this resulted from uncertainties associated with estimating virion and cell volumes or real differences. Virions were highly stable and did not \"leak\" dNTPs as associated dNTPs were not released, even after incubation at 60°C for 90 min or several freeze-thaw cycles, a result that implies diffusion-mediated import of dNTPs into virions is also unlikely. Overall, results show that dNTPs in intact virions are at or below concentrations in cells, and even the most abundant dNTP (dTTP) is present at ~1 copy per virion. This precludes significant DNA synthesis in intact virions, although it is important to note that our assays may not represent all virion states. The results support a mechanism where dNTPs are passively captured during virion budding.</p><p><strong>Importance: </strong>HIV virions presumably package small molecules (e.g., amino acids, cations, and nucleotides) passively during budding. Therefore, they would be present in virions at cellular levels, unless there is a mechanism for concentration or exclusion of the molecule (e.g., inositol hexakisphosphate (IP6), which stabilizes the viral capsid, is present at several-fold greater concentration in the virion compared with cells). Reports of DNA synthesis occurring in HIV virions suggest that HIV may also package dNTPs at levels much higher than predicted by their cellular concentrations, or virions are permeable to dNTPs. However, we show here that virion dNTP levels are at or below cellular levels with 1 or fewer molecules of each dNTP in an average virion. Furthermore, virions did not leak dNTPs when exposed to elevated temperatures or freeze-thawing, suggesting that they were not permeable. The results suggest that virions demonstrating significant DNA synthesis may be structurally altered relative to those measured here.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0056425"},"PeriodicalIF":4.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637391","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":"Breadth of antibody activity elicited by an influenza B hemagglutinin vaccine is influenced by pre-existing immune responses to influenza B viruses.","authors":"Michael A Carlock, Spencer R Pierce, Ted M Ross","doi":"10.1128/jvi.00705-25","DOIUrl":"https://doi.org/10.1128/jvi.00705-25","url":null,"abstract":"<p><p>Most people are exposed to influenza A and influenza B viruses (IBV) at an early age through natural infection or vaccination. These previous exposures can shape future immune responses and the ability to either recall memory B cells or generate <i>de novo</i> immune responses. Therefore, it is important to consider pre-existing immunity when testing vaccine candidates. The B/Victoria (B/VIC) and the B/Yamagata (B/YAM) lineages circulated in the human population between 1987 and 2020 until the B/YAM lineage stopped circulating following the coronavirus disease 2019 pandemic. Most people born prior to 2020 have pre-existing immune responses to both lineages of IBV. Therefore, in this report, the impact of vaccine-induced antibodies was explored in mice with pre-existing immune responses to B/YAM or B/VIC viruses alone or in combination. The recalled B cell responses induced by modern wild-type hemagglutinin (HA) vaccines from each IBV lineage were compared to the recalled B cell responses elicited by a broadly reactive antigen, B-COBRA-2 (BC2) HA, which elicits cross-lineage neutralizing antibodies. This report highlights the lineage specificity of immunological imprinting with IBV and demonstrates the antigen-specific activation of antibody-secreting B cells by broadly reactive antigens.</p><p><strong>Importance: </strong>This report demonstrates how varying immunological backgrounds to influenza B virus influence vaccine-induced responses in mice. It further highlights that a broadly reactive influenza B virus hemagglutinin (HA) antigen stimulates higher levels of IgM-secreting cells compared to wild-type HA antigens.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0070525"},"PeriodicalIF":4.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637392","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":"Rationally designed self-assembled peptide nanofibers provoke robust humoral immunity against nervous necrosis virus.","authors":"Chen Zhang, Yong-Can Zhou, Wen-Ye Song, Xin-Xin Liu, Hai-Hua Peng, Yun Sun","doi":"10.1128/jvi.00319-25","DOIUrl":"https://doi.org/10.1128/jvi.00319-25","url":null,"abstract":"<p><p>Nervous necrosis virus (NNV) poses devastating mortality risks to almost all marine fish, causing significant economic losses to the marine fish aquaculture industry, particularly in juvenile groupers. However, no effective NNV vaccine is available. To counter this, we report a smart strategy of a rationally designed modular peptide vaccine platform (CP^64-83-Q11) that recapitulates the antigen peptide CP^64-83 and a Q11 self-assembling domain. An anti-NNV phage antibody library was constructed and used for screening anti-NNV antibody. Bioinformatics and surface-plasmon resonance were utilized to identify the antigen epitope of NNV. Furthermore, the CP^64-83-Q11 nanofiber was designed and constructed. The cellular and tissular uptake of CP^64-83-Q11 was analyzed i<i>n vitro</i> and <i>in vivo</i>. Moreover, the immunogenicity and the protective efficacy of the CP^64-83-Q11 nanofibers were evaluated by determining the expression of antigen-presenting indicators, antibody levels, and response to viral challenge to vaccinated fish. It has been proven that CP^64-83-Q11 nanofiber could efficiently deliver antigen peptide to immune tissues and induce robust humoral immunity against NNV infection, which provided a protection rate of approximately 88%. This study provides an effective strategy for aquatic vaccine design, which will be beneficial for the application and development of vaccines in the aquaculture industry.IMPORTANCEViral diseases have constantly caused a great threat to global public health, resulting in an urgent need for effective vaccines. However, the current viral vaccines are often showing low immunogenicity. NNV, a serious threat to almost marine fish, was used as a viral model in this study. To address the threat of NNV, an anti-NNV antibody phage library was constructed and used for anti-NNV antibody biopanning. Based on bioinformatics and surface-plasmon resonance, we validated an antigen peptide for NNV (CP^64-83) with high-affinity binding ability to the anti-NNV antibody. Moreover, a modular peptide vaccine delivery platform (CP^64-83-Q11) was rationally designed using phage display technology and bioinformatics. CP^64-83-Q11 could efficiently deliver into immune tissues and provide effective protection against NNV infection by inducing a significant level of humoral immunity. This study offers new insights into rational viral vaccine design for fish, which could provide methods for the prevention and treatment of animal viral diseases.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0031925"},"PeriodicalIF":4.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637437","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":"Teaching an old vector new tricks: the surprising versatility of AAV vaccines.","authors":"Stephen M Winston, Kristin B Wiggins, Stacey Schultz-Cherry, Andrew M Davidoff","doi":"10.1128/jvi.00730-25","DOIUrl":"https://doi.org/10.1128/jvi.00730-25","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) has proven its clinical efficacy in the realm of gene therapy, resulting in seven FDA-approved gene therapies. While AAV gene transfer research has predominantly focused on its utility in monogenic disorders, AAV vectors have been used as a platform for vaccines in over 50 preclinical studies over the last 25 years. Recombinant AAV-based vaccines have demonstrated induction and durability of antigen-specific adaptive immune responses in a variety of preclinical models. This mini-review serves as a comprehensive discussion of the basics of vaccine vector design and experimental considerations, highlighting engineering efforts to improve AAV vaccine efficacy, along with the known advantages and disadvantages of AAV-based vaccines from published pre-clinical studies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0073025"},"PeriodicalIF":4.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626665","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":"Novel insights into immune checkpoints in HIV/SHIV infection: from SHIV_SF162P3-infected elite controllers to therapeutic strategy.","authors":"Yuting Sun, Chenbo Yang, Peiwen Liu, Zhe Cong, Jiahui Luo, Ling Tong, Jingjing Zhang, Jiahan Lu, Ziqing Jia, Lin Zhu, Qiuhan Lu, Ting Chen, Qiang Wei, Dan Li, Rui Hou, Jing Xue","doi":"10.1128/jvi.00785-25","DOIUrl":"https://doi.org/10.1128/jvi.00785-25","url":null,"abstract":"<p><p>During chronic HIV-1 infection, the upregulation of immune checkpoints (ICs) on lymphocytes contributes to persistent immune dysfunction, T-cell exhaustion, and inadequate virological control, highlighting the potential role of ICs in HIV functional cure strategy. Despite extensive research on ICs, the expression dynamics and immunological impact of ICs in natural HIV/SHIV infection, particularly among antiretroviral therapy (ART)-free elite controllers (ECs), remain poorly understood. In this study, we monitored a cohort of SHIV_SF162P3-infected rhesus macaques (RMs), identifying four ECs and four progressors (PGs) through longitudinal evaluation. We observed low-level expression of ICs in both peripheral blood and lymph nodes of ECs, characterized by a particularly pronounced restriction in the expression of TIGIT and BTLA. This attenuated IC profile correlated with enhanced T-cell functionality, reduced exhaustion markers, and reduced viral reservoirs in peripheral and lymphoid tissues. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation. Collectively, our findings establish a dual role for ICs in perpetuating T-cell exhaustion and viral reservoir persistence, paving the way for IC blockade in future HIV cure strategies.IMPORTANCERhesus macaques spontaneously controlling simian-human immunodeficiency virus (SHIV) without antiretroviral therapy have low-level expression of immune molecules (ICs), characterized by TIGIT and BTLA. These molecules are linked to enhanced immune function and reduced viral presence in peripheral blood and lymph nodes. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation in both humans and macaques. Blocking TIGIT improved polyfunctional T-cell responses, thereby offering a potential new treatment strategy and providing critical insights for developing a functional HIV cure.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0078525"},"PeriodicalIF":4.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600872","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":"CX1/BtSY2 and BANAL-20-52 exhibit broader receptor binding and higher affinities to multiple animal ACE2 orthologs than SARS-CoV-2 prototype.","authors":"Zepeng Xu, Linjie Li, Yuhang Gu, Dedong Li, Jianxun Qi, Kefang Liu, Chu-Xia Deng, George Fu Gao","doi":"10.1128/jvi.00283-25","DOIUrl":"https://doi.org/10.1128/jvi.00283-25","url":null,"abstract":"<p><p>Animal coronaviruses (CoVs) CX1 (formerly named BtSY2) and BANAL-20-52 are phylogenetically closely related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and CX1 is the first observed animal betaCoV carrying naturally occurring Y501 in its receptor-binding domain (RBD) of the spike (S) protein, a residue related to human adaptation and broader host range. We evaluated the ACE2 usage of CX1 and BANAL-20-52 and observed broader receptor binding spectra and higher affinities to most of the tested animal ACE2 orthologs than the SARS-CoV-2 prototype. Determination of the cryo-EM structures of their S proteins and RBD/hACE2 complexes reveals that Y501 is inter-replaceable with H498 substitution while synergetic with R498 for human ACE2 binding. These results provide further structural insights into SARS-CoV-2 receptor recognition and address the importance of surveillance on potential emerging CoVs.IMPORTANCESince the outbreak of COVID-19, forewarning and prevention of the next pandemic have been widely discussed. Coronaviruses (CoVs) CX1 (formerly named BtSY2) and BANAL-20-52 are phylogenetically closely related to SARS-CoV-2. Particularly, CX1 is the first SARS-CoV-2-related CoV containing Y501 in its receptor-binding domain (RBD) of the spike (S) protein. This study evaluated the interspecies transmission potential of the two CoVs and structurally elucidated the interplay between two RBD residues 498 and 501 on ACE2 binding, further highlighting the importance of surveillance on zoonotic CoVs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0028325"},"PeriodicalIF":4.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600871","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":"The HCMV tegument protein UL88 degrades MyD88 and reduces innate immune activation.","authors":"Rinki Kumar, Irene E Reider, Madison Martin, Julia S Simpson, Nicholas J Buchkovich, Christopher C Norbury","doi":"10.1128/jvi.00414-25","DOIUrl":"https://doi.org/10.1128/jvi.00414-25","url":null,"abstract":"<p><p>The human cytomegalovirus (HCMV) encodes the tegument protein UL88, which supports virus spread by mediating the degradation of the innate immune signaling adapter protein, myeloid differentiation primary response 88 (MyD88). MyD88 transduces signals in multiple innate immune pathways, including acting downstream of pattern recognition receptors and IL-1 cytokine family members. MyD88 is rapidly and robustly upregulated following exposure to HCMV, irrespective of viral gene expression and, even after infection, primarily within uninfected cells in a culture. However, UL88 was required to downregulate cellular MyD88 protein levels as HCMV spread through a culture. The N-terminal 181 amino acids of UL88 were required to associate with and downregulate MyD88 protein. MyD88 expression significantly suppressed virus spread by triggering the production of a heat-labile soluble factor. This factor was produced between ~3 and 6 days after initial infection and did not increase the expression of well-characterized interferon-stimulated genes (ISGs). Indeed, increased MyD88 expression downregulated the expression of almost all ISGs examined. UL88 overexpression suppressed IL-1β-induced NF-κB activation within a cell. UL88 also suppressed virus-induced translocation of NF-κB to the nucleus of uninfected neighboring cells in an infected monolayer. Furthermore, UL88 overexpression was required for effective HCMV spread following transfer of the virus from monocytes to a fibroblast monolayer. These data indicate that UL88 is a novel antagonist of the immune response that acts to enhance the natural spread of HCMV by targeting MyD88 and provides vital insight into the innate immune responses that can control HCMV spread.IMPORTANCEThe significant role of many viral genes encoded by HCMV that are not essential for replication in cell culture is often overlooked. Our study reveals the importance of UL88 for regulating the innate immune response by showing evidence for interaction with and downregulation of MyD88 protein. The UL88-dependent regulation of MyD88 is physiologically relevant, as infection is enhanced in the absence of MyD88, and spread from myeloid cells to fibroblasts is blunted in the absence of UL88. These results highlight yet another important interaction between HCMV and the immune system.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0041425"},"PeriodicalIF":4.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600873","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":"ICAM-1-mediated Src signaling pathway plays a pivotal role in encephalomyocarditis virus entry.","authors":"Ruiya Lian, Xueer Dou, Na Wang, Shasha Li, Jingying Xie, Xiangrong Li, Yanmei Yang, Yanqiao Wen, Huixia Li, Ruofei Feng","doi":"10.1128/jvi.00715-25","DOIUrl":"https://doi.org/10.1128/jvi.00715-25","url":null,"abstract":"<p><p>Encephalomyocarditis virus (EMCV), a potential zoonotic pathogen with a broad host range, has been reported to enter cells via caveolin-mediated endocytosis (CavME), a process initiated by caveolae detachment from the plasma membrane. However, the molecular mechanism underlying EMCV's cellular entry remains incompletely characterized. Here, we identified for the first time that the overexpression of Src kinase and Fyn kinase individually enhanced the replication and proliferation of EMCV. The treatment of specific small interfering RNA or inhibitors resulted in the downregulation of EMCV internalization, indicating the involvement of Src, Fyn, and Ezrin in the viral entry process. By treating different cell lines (BHK-21, hCMEC/D3, and PK15 cells) from various species with inhibitors of Src or Ezrin, as well as using siCav-1, and subsequently performing EMCV invasion experiments, we demonstrated the sequential activation of Src, Ezrin, and Cav-1 during EMCV internalization, indicating that this signaling pathway is widely present during EMCV infection of human-, hamster-, and pig-derived cells. Interestingly, the candidate receptor protein ICAM-1 interacts with Src and regulates its phosphorylation. Compared to the wild-type cells, lower levels of the phosphorylation of Src, Ezrin, and Cav-1 induced by EMCV were observed in ICAM-1 knockout BHK-21 cells. These findings indicate that EMCV entry into BHK-21 cells relies on the activation of the ICAM-1-Src-Ezrin-Cav-1 pathway. Our study first elucidates the molecular mechanism of EMCV invading into BHK-21 cells, providing potential targets for limiting EMCV infection and further refining the regulatory mechanism of the Src pathway on CavME.IMPORTANCEEMCV has a wide host range and is a potential zoonotic pathogen, yet the mechanism of its entry into cells remains unclear. This study has found that the host proteins Src, Fyn, and Ezrin are involved in viral replication and proliferation, and their activity inhibitors hinder EMCV invasion into cells. With the participation of the cell surface adhesion factor ICAM-1, EMCV infects host cells by sequentially activating the phosphorylation of Src, Ezrin, and Cav-1, mediating the entry of EMCV into host cells through CavME. We have demonstrated for the first time the existence of an ICAM-1-Src-Ezrin-Cav-1 signaling pathway during EMCV entry into susceptible cells, which mediates the internalization process of the virus. Our research not only unravels the molecular mechanism of EMCV invasion, filling a gap in related research, but also provides a theoretical basis for the development of specific antiviral therapeutics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0071525"},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591541","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":"PEDV Nsp14 induces mitophagy-mediated degradation of MAVS to antagonize host innate immunity and facilitate viral proliferation.","authors":"Lei Yang, Qisheng Qian, Yan-Gang Sun, Xin-Xin Chen, Guangxu Xing, Jia-Qing Zhang, Bao-Song Xing, Songlin Qiao, Rui Li, Gaiping Zhang","doi":"10.1128/jvi.00498-25","DOIUrl":"https://doi.org/10.1128/jvi.00498-25","url":null,"abstract":"<p><p>Porcine epidemic diarrhea virus (PEDV) leads to a high mortality in neonatal piglets and causes serious harm to the global swine industry. PEDV has been shown to exploit diverse strategies for antagonism of host innate immunity and promotion of self-replication. However, the underlying mechanisms involved in PEDV immunosuppression remain to be fully elucidated. The current study reveals that PEDV triggers mitophagy to suppress host innate immune responses and facilitate viral proliferation. Mechanistically, PEDV non-structural protein (Nsp) 14 was identified to mediate the interaction between the mitophagy receptor NDP52 and mitochondrial outer membrane protein TOM20 to induce mitophagy. Subsequently, Nsp14-induced mitophagy resulted in the degradation of mitochondrial antiviral signaling protein (MAVS) to suppress interferon-β (IFN-β) production and promote viral propagation. These findings deepen the understanding of PEDV pathogenesis and provide novel targets for the development of antiviral avenues.</p><p><strong>Importance: </strong>The global pig farming industry has suffered huge economic losses from PEDV, underscoring an urgent need for in-depth research on its pathogenesis. Host innate immunity functions as the first line of defense against PEDV propagation, and PEDV has developed multiple countermeasures to dampen host antiviral responses. Here, we found that PEDV Nsp14 induced mitophagy via mediating the interaction between NDP52 and TOM20, which led to MAVS degradation and hampered IFN-β production. Therefore, our work unveils a novel mechanism by which PEDV antagonizes host innate immunity to facilitate its proliferation and is beneficial for the prevention and control of the virus.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0049825"},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591542","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}