Journal of Virology最新文献

{"title":"Highly pathogenic avian influenza H5N1: history, current situation, and outlook.","authors":"Florian Krammer, Enikö Hermann, Angela L Rasmussen","doi":"10.1128/jvi.02209-24","DOIUrl":"https://doi.org/10.1128/jvi.02209-24","url":null,"abstract":"<p><p>The H5N1 avian panzootic has resulted in cross-species transmission to birds and mammals, causing outbreaks in wildlife, poultry, and US dairy cattle with a range of host-dependent pathogenic outcomes. Although no human-to-human transmission has been observed, the rising number of zoonotic human cases creates opportunities for adaptive mutation or reassortment. This Gem explores the history, evolution, virology, and epidemiology of clade 2.3.4.4b H5N1 relative to its pandemic potential. Pandemic risk reduction measures are urgently required.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0220924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719977","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":"Restriction of influenza A virus replication by host DCAF7-CRL4B axis.","authors":"Lei Yu, Yong Jiang, Hongyu Rang, Xueyun Wang, Yumeng Cai, Haojie Yan, Shuwen Wu, Ke Lan","doi":"10.1128/jvi.00133-25","DOIUrl":"https://doi.org/10.1128/jvi.00133-25","url":null,"abstract":"<p><p>The balance between cellular defense and viral escape determines the fate of influenza A virus (IAV) infection. Viral polymerase activity is critical for the replication and propagation of IAV. The antiviral strategies of host cells against IAV infection have not been fully elucidated. Here, we identified DCAF7 as an antiviral factor for IAV, which inhibits the replication of H1N1 and H3N2. Mechanistically, DCAF7 weakens the viral heterotrimer polymerase activity and restricts IAV replication and transcription. DCAF7 as a substrate recognition receptor forms a complete CRL4B^DCAF7 E3 ligase with the CRL4B E3 complex to promote K48-linked polyubiquitination of the viral polymerase subunit PA at the K609 site and its degradation. We also showed that a specific cullin-RING E3 ligase (CRL) inhibitor MLN4924 upregulates the protein level of PA and promotes the replication of IAV <i>in vivo</i>. Moreover, activation of CUL4B by etoposide promotes the degradation of PA and inhibits IAV replication <i>in vivo</i>. Importantly, we found that viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. Taken together, these findings reveal a new mechanism of host resistance to IAV infection and suggest that regulation of the DCAF7-CRL4B axis is a potential target for antivirals.</p><p><strong>Importance: </strong>Until now, the key host factors that affect IAV polymerase have not been fully elucidated. In this study, we identified host DCAF7 as a novel restriction factor for IAV replication. Importantly, DCAF7 acts as a substrate recognition receptor to recruit CRL4B E3 ligase to mediate the degradation of PA through the ubiquitin-proteasome pathway. Further exploration demonstrated that a specific cullin-RING E3 ligase inhibitor MLN4924 promotes IAV replication <i>in vivo</i>, and activation of CUL4B by etoposide inhibits IAV replication <i>in vivo</i>. Notably, we found that the viral NS1 protein decreases DCAF7 level to impair its antiviral efficacy. These findings elucidate the critical function and mechanism of the DCAF7-CRL4B axis in IAV replication, reveal a novel host anti-IAV mechanism, and provide new anti-influenza drug development strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0013325"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719996","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":"ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation.","authors":"Li Tian, Zhizhong Mi, Weijing Yang, Jing Chen, Xiulong Wei, Wenyan Zhang, Zhaolong Li","doi":"10.1128/jvi.00030-25","DOIUrl":"https://doi.org/10.1128/jvi.00030-25","url":null,"abstract":"<p><p>Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease, particularly affecting pediatric populations worldwide. The role of ZYG11B, a CUL2-complex-associated E3 ubiquitin ligase from the Zyg-11 family, in antiviral defense against EV71 remains unclear. To our knowledge, this study is the first to reveal that ZYG11B targets EV71 VP1 for proteasomal degradation via the ubiquitin-proteasome pathway, with CRL2^ZYG11B complex activity specifically driving K33-linked ubiquitination. Mass spectrometry and immunoprecipitation analyses confirmed the interaction between ZYG11B and VP1 and identified key domains required for binding both VP1 and CUL2. Comparative analyses showed that VP1 ubiquitination sites are highly conserved across related enteroviruses, including CA6, CA16, and EVD68. Functional assays further demonstrated that ZYG11B restricts these viruses, highlighting its potential as a broad-spectrum antiviral target. These findings establish ZYG11B as a critical effector in host antiviral responses and support its therapeutic potential for managing enterovirus infections.</p><p><strong>Importance: </strong>E3 ubiquitin ligases and deubiquitinases have become important topics of competition between viruses and hosts. Here, we identified CRL2^ZYG11B as an E3 ubiquitin ligase complex capable of degrading structural protein VP1 of enteroviruses, making ZYG11B a broad-spectrum antiviral factor. We first proposed the inhibitory effect of ZYG11B on viruses and identified the structural domains of ZYG11B connecting substrates and CUL2, providing new targets for the design of antiviral drugs.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0003025"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709994","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":"Cathepsins in cellular entry of human pathogenic viruses.","authors":"Tejal Pathak, Sampurna Pal, Indranil Banerjee","doi":"10.1128/jvi.01642-24","DOIUrl":"https://doi.org/10.1128/jvi.01642-24","url":null,"abstract":"<p><p>In the life cycle of a virus, host cell entry represents the first step that a virus needs to undertake to gain access to the cell interior for replication. Once a virus attaches itself to its target cell receptor, it activates endogenous cellular responses and exploits host cell factors for its internalization, fusion, and genome release. Among the host factors that critically contribute to the viral entry processes are cathepsins, which are the most abundant endo/lysosomal proteases with diverse physiological functions. This review summarizes previous findings on how different cathepsins contribute to the host cell entry of human pathogenic viruses, focusing on their specific roles in the entry processes of both enveloped and non-enveloped RNA viruses. A comprehensive knowledge of the functions of different cathepsins in viral entry will provide valuable insights into the molecular mechanisms underlying viral infections and can be useful in the development of new antiviral strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0164224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710471","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":"Murine nasal-associated lymphoid tissue (NALT) harbors human alphaherpesvirus 1 (HSV-1) DNA during latency, and dexamethasone triggers viral replication.","authors":"Kelly S Harrison, Shannon R Cowan, Clinton Jones","doi":"10.1128/jvi.02251-24","DOIUrl":"https://doi.org/10.1128/jvi.02251-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Human alphaherpesvirus 1 (HSV-1) acute infection causes conjunctivitis, encephalitis, genital lesions, and herpes esophagitis. Following acute infection, HSV-1 and other alpha-herpesvirinae subfamily members establish life-long latency in neurons within the trigeminal ganglia and central nervous system. Notably, certain animal alpha-herpesvirinae subfamily members, including bovine alphaherpesvirus 1 (BoHV-1), canine herpesvirus 1, equine herpesvirus 4, and pseudorabies virus, establish a quiescent/latent infection in tonsils. BoHV-1 viral gene expression and virus shedding from tonsils also occur during reactivation from latency in calves. Consequently, we tested whether nasopharyngeal lymphoid tissue (NALT) harbors HSV-1 DNA in latently infected mice because it is structurally and functionally comparable with tonsils. NALT prepared from latently infected mice consistently contained viral DNA, but infectious virus was not detected. In contrast to latently infected TG neurons, the HSV-1 latency-associated transcript was not detected in NALT of latently infected mice. HSV-1 DNA levels, immediate early RNA expression, and virus shedding were readily detected when NALT explants were cultured with a medium containing the synthetic corticosteroid dexamethasone for 48 h. Increased viral DNA and virus production were not detected in NALT explants when incubated with a medium lacking dexamethasone. Sorting cells from NALT of HSV-1 latently infected mice revealed that dendritic cells, microfold cells, and natural killer cells, but not B or T cells, harbor HSV-1 DNA, and infectious virus was readily detected when cultured in medium containing dexamethasone. In summary, certain NALT cells consistently contain viral DNA in latently infected mice, and dexamethasone triggers viral gene expression and virus production.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Human alphaherpesvirus 1 (HSV-1) acute infection causes various diseases, including herpes esophagitis. HSV-1 subsequently establishes lifelong latency in neurons within the trigeminal ganglia and central nervous system. Viral DNA, but not infectious virus, was consistently detected in nasopharyngeal lymphoid tissue (NALT) of latently infected mice. NALT is structurally and functionally comparable with the tonsils of other mammals, including humans. RNA and protein expression of infected cell protein 0 (ICP0) and ICP4 plus virus production were consistently detected when NALT explants were cultured with a medium containing dexamethasone, a synthetic corticosteroid. Sorting NALT cells from HSV-1 latently infected mice revealed dendritic cells, microfold cells, and natural killer cells that harbor HSV-1 DNA. Virus shedding was readily detected when viral DNA-positive NALT cells were cultured in a medium containing dexamethasone. These studies revealed that specific NALT cells harbor viral DNA, and dexamethasone triggered viral replication and virus production, suggesting that reactivation from a latent or qu","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0225124"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709612","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":"Herpes simplex virus 1 envelope glycoprotein C shields glycoprotein D to protect virions from entry-blocking antibodies.","authors":"McKenna A Hull, Suzanne M Pritchard, Anthony V Nicola","doi":"10.1128/jvi.00090-25","DOIUrl":"10.1128/jvi.00090-25","url":null,"abstract":"<p><p>Herpes simplex virus 1 (HSV-1) gD interaction with the host cell receptor nectin-1 triggers the membrane fusion cascade during viral entry. Potent neutralizing antibodies to gD prevent receptor-binding or prevent gD interaction with gH/gL critical for fusion. HSV has many strategies to evade host immune responses. We investigated the ability of virion envelope gC to protect envelope gD from antibody neutralization. HSV-1 lacking gC was more sensitive to neutralization by anti-gD monoclonal antibodies than a wild-type rescuant virus. gD in the HSV-1 gC-null viral envelope had enhanced reactivity to anti-gD antibodies compared to wild type. Soluble nectin-1 bound similar to HSV-1 particles regardless of the presence of gC in the envelope. However, entry of HSV-1 ΔgC was more sensitive to inhibition by soluble nectin-1 receptor. The viral membrane protein composition of HSV-1 ΔgC is equivalent to that of wild type, suggesting that the lack of gC is responsible for the increased reactivity of gD-specific antibodies and the consequent increased susceptibility to neutralization by those antibodies. Together, the results suggest that gC in the HSV-1 envelope shields both receptor-binding domains and gH/gL-interacting domains of gD from neutralizing antibodies, facilitating HSV cell entry.IMPORTANCEHSV-1 causes lifelong infections. There is no vaccine and no cure. Understanding HSV immune evasion strategies is an important goal. HSV-1 gC is a multi-functional envelope glycoprotein. This study suggests that virion gC physically shields neighboring gD from antibodies, including neutralizing monoclonal antibodies. This mechanism may allow HSV to escape immune detection, promoting HSV infection in the host.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0009025"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710427","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":"Coordination of the host Vps4-Vta1 complex and the viral core protein Ac93 facilitates entry of Autographa californica multiple nucleopolyhedrovirus budded virions.","authors":"Xiaorong Yue, Ning Ji, Yixiang Ma, Qianlong Yu, Lisha Bai, Zhaofei Li","doi":"10.1128/jvi.02182-24","DOIUrl":"https://doi.org/10.1128/jvi.02182-24","url":null,"abstract":"<p><p>The endosomal sorting complex required for transport (ESCRT) is a protein machine mediating membrane scission. In intraluminal vesicle (ILV) formation, ESCRT-0 targets cargoes and recruits ESCRT-I/-II to create membrane invagination, whereas ESCRT-III coordinates with the AAA ATPase Vps4 and its cofactor Vta1 to catalyze the membrane fission. Recently, ESCRT-I/-III and Vps4 were found to be involved in the entry of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV). However, the necessity of other ESCRT components and the interplay of viral proteins and ESCRTs in regulating the virus entry remain elusive. Here, we identified ESCRT-0 (Hse1 and Vps27), ESCRT-II (Vps22, Vps25, and Vps36), and Vta1 of <i>Spodoptera frugiperda</i>. RNAi depletion of Vta1 but not the components of ESCRT-0 or ESCRT-II in Sf9 cells significantly reduced budded virus (BV) production. Quantitative PCR together with confocal microscopy analyses indicated that Vta1 was required for internalization and endosomal trafficking of BV. In the late phase of infection, although Vps4 and Vta1 were both distributed to the nucleus and at the plasma membrane, depletion of Vta1 did not affect BV release. Further analysis revealed that 7 of 14 BV envelope proteins (Ac75, Ac93, E25, F-like, P33, P48, and vUbiquitin) interacted with Vps4 and Vta1. Intriguingly, Ac93 adopted a similar mode as ESCRT-III proteins to interact with the microtubule-interacting and transport (MIT) domains of Vps4 and Vta1 via its C-terminal MIT-interacting motifs (MIM1), and the interactions were necessary for BV internalization. Together, our studies highlight the coordination of Vps4-Vta1 and Ac93, and probably other BV envelope proteins, in facilitating entry of AcMNPV.IMPORTANCEThe endosomal sorting complex required for transport (ESCRT) system is involved in the entry of diverse DNA and RNA viruses. However, the interplay of viral proteins and ESCRTs in promoting virus endocytosis remains largely unknown. Here, we found that the ESCRT early acting factors ESCRT-0/-II were not necessary for infectious budded virus (BV) production of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). In contrast, the Vps4 cofactor Vta1 was required for entry but not egress of BV. Several core or essential BV envelope proteins were identified to interact with Vps4 and Vta1. Among them, Ac93 plays a central role in connecting other viral proteins and mimics ESCRT-III proteins to interact with Vps4-Vta1, facilitating entry of BV virions. These studies provide evidence for the coordination of viral proteins and ESCRTs in regulating entry of large enveloped DNA viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0218224"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710474","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":"Role of glycosylation mutations at the N-terminal domain of SARS-CoV-2 XEC variant in immune evasion, cell-cell fusion, and spike stability.","authors":"Pei Li, Julia N Faraone, Cheng Chih Hsu, Michelle Chamblee, Yajie Liu, Yi-Min Zheng, Yan Xu, Claire Carlin, Jeffrey C Horowitz, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Daniel Jones, Jianrong Li, Richard J Gumina, Joseph S Bednash, Kai Xu, Shan-Lu Liu","doi":"10.1128/jvi.00242-25","DOIUrl":"10.1128/jvi.00242-25","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, producing new variants that drive global coronavirus disease 2019 surges. XEC, a recombinant of KS.1.1 and KP.3.3, contains T22N and F59S mutations in the spike protein's N-terminal domain (NTD). The T22N mutation, similar to the DelS31 mutation in KP.3.1.1, introduces a potential N-linked glycosylation site in XEC. In this study, we examined the neutralizing antibody (nAb) response and mutation effects in sera from bivalent-vaccinated healthcare workers, BA.2.86/JN.1 wave-infected patients, and XBB.1.5 monovalent-vaccinated hamsters, assessing responses to XEC alongside D614G, JN.1, KP.3, and KP.3.1.1. XEC demonstrated significantly reduced neutralization titers across all cohorts, largely due to the F59S mutation. Notably, removal of glycosylation sites in XEC and KP.3.1.1 substantially restored nAb titers. Antigenic cartography analysis revealed XEC to be more antigenically distinct from its common ancestral BA.2.86/JN.1 compared to KP.3.1.1, with the F59S mutation as a determining factor. Similar to KP.3.1.1, XEC showed reduced cell-cell fusion relative to its parental KP.3, a change attributed to the T22N glycosylation. We also observed reduced S1 shedding for XEC and KP.3.1.1, which was reversed by ablation of T22N and DelS31 glycosylation mutations, respectively. Molecular modeling suggests that T22N and F59S mutations of XEC alter hydrophobic interactions with adjacent spike protein residues, impacting both conformational stability and neutralization. Overall, our findings underscore the pivotal role of NTD mutations in shaping SARS-CoV-2 spike biology and immune escape mechanisms.IMPORTANCEThe continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of novel variants with enhanced immune evasion properties, posing challenges for current vaccination strategies. This study identifies key N-terminal domain (NTD) mutations, particularly T22N and F59S in the recent XEC variant, which significantly impacts antigenicity, neutralization, and spike protein stability. The introduction of an N-linked glycosylation site through T22N, along with the antigenic shift driven by F59S, highlights how subtle mutations can drastically alter viral immune recognition. By demonstrating that glycosylation site removal restores neutralization sensitivity, this work provides crucial insights into the molecular mechanisms governing antibody escape. Additionally, the observed effects on spike protein shedding and cell-cell fusion contribute to a broader understanding of variant fitness and transmissibility. These findings emphasize the importance of monitoring NTD mutations in emerging SARS-CoV-2 lineages and support the need for adaptive vaccine designs to counteract ongoing viral evolution.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0024225"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709842","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":"Early 2022 breakthrough infection sera from India target the conserved cryptic class 5 epitope to counteract immune escape by SARS-CoV-2 variants.","authors":"Indrani Das Jana, Kawkab Kanjo, Subhanita Roy, Munmun Bhasin, Shatarupa Bhattacharya, Indranath Banerjee, Subhasis Jana, Arjun Chatterjee, Alok Kumar Chakrabarti, Suman Chakraborty, Budhaditya Mukherjee, Raghavan Varadarajan, Arindam Mondal","doi":"10.1128/jvi.00051-25","DOIUrl":"https://doi.org/10.1128/jvi.00051-25","url":null,"abstract":"<p><p>During the coronavirus disease 2019 (COVID-19) pandemic, the vast majority of epitope mapping studies have focused on sera from mRNA-vaccinated populations from high-income countries. In contrast, here, we report an analysis of 164 serum samples isolated from patients with breakthrough infection in India during early 2022 who received two doses of the ChAdOx viral vector vaccine. Sera were screened for neutralization breadth against wild-type (WT), Kappa, Delta, and Omicron BA.1 viruses. Three sera with the highest neutralization breadth and potency were selected for epitope mapping, using charged scanning mutagenesis coupled with yeast surface display and next-generation sequencing. The mapped sera primarily targeted the recently identified class 5 cryptic epitope and, to a lesser extent, the class 1 and class 4 epitopes. The class 5 epitope is completely conserved across all severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and for most sarbecoviruses. Based on these observations, an additional 26 sera were characterized, and all showed a broad neutralizing activity, including against XBB.1.5. This is in contrast with the results obtained with the sera from individuals receiving multiple doses of original and updated mRNA vaccines, where impaired neutralization of XBB and later variants of concern (VOCs) were observed. Our study demonstrates that two doses of the ChAdOx vaccine in a highly exposed population were sufficient to drive substantial neutralization breadth against emerging and upcoming variants of concern. These data highlight the important role of hybrid immunity in conferring broad protection and inform future vaccine strategies to protect against rapidly mutating viruses.</p><p><strong>Importance: </strong>Worldwide implementation of coronavirus disease 2019 (COVID-19) vaccines and the parallel emergence of newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have shaped the humoral immune response in a population-specific manner. While characterizing this immune response is important for monitoring disease progression at the population level, it is also imperative for developing effective countermeasures in the form of novel vaccines and therapeutics. India has implemented the world's second largest COVID-19 vaccination drive and encountered a large number of post-vaccination \"breakthrough\" infections. From a cohort of patients with breakthrough infection, we identified individuals whose sera showed broadly neutralizing immunity against different SARS-CoV-2 variants. Interestingly, these sera primarily target a novel cryptic epitope, which was not identified in previous population-level studies conducted in Western countries. This rare cryptic epitope remains conserved across all SARS-CoV-2 variants, including recently emerged ones and for the SARS-like coronaviruses that may cause future outbreaks, thus representing a potential target for future vaccines.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0005125"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710423","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":"African swine fever virus I177L induces host inflammatory responses by facilitating the TRAF6-TAK1 axis and NLRP3 inflammasome assembly.","authors":"Pan-Xue Wu, Wen-Ping Yang, Tao Feng, Jing Zhang, Guo-Qiang Zhu, Xu-Guang Du, Yi Ru, Yao-Feng Zhao, Sen Wu, Dan Li, Hai-Xue Zheng","doi":"10.1128/jvi.02080-24","DOIUrl":"https://doi.org/10.1128/jvi.02080-24","url":null,"abstract":"<p><p>African swine fever virus (ASFV) is the pathogen of African swine fever (ASF), and its infection causes a lethal disease in pigs, with severe pathological lesions. These changes indicate excessive inflammatory responses in infected pigs, which is the main cause of death, but the ASFV proteins worked in this physiological process and the mechanisms underlying ASFV-induced inflammation remain unclear. Here, we identify that viral I177L works in these inflammatory responses. Mechanistically, I177L facilitates TRAF6 ubiquitination that enhances its binding to TAK1, which promotes TAK1 ubiquitination and phosphorylation. These processes depend on the E3 ubiquitin ligase activity of TRAF6. The upregulation of I177L to TRAF6-TAK1 interaction and TAK1 activation is responsible for I177L's activated effect on the NF-κB signaling pathway. Additionally, I177L promotes assembly of the NLRP3 inflammasome and ASC oligomerization, thus leading to the activation of the NLRP3 inflammasome and the production and secretion of mature IL-1β. TAK1 inhibition efficiently reverses ASFV-activated NF-κB signaling and inflammatory responses and suppresses ASFV replication. Furthermore, I177L-deficient ASFV induces milder inflammatory responses in pigs compared with parental ASFV, which still protects pigs against ASFV challenge. The finding confirms ASFV I177L as an important proinflammatory protein <i>in vitro</i> and <i>in vivo</i> and reveals a key mechanism underlying ASFV-mediated inflammatory responses for the first time, which enriches our knowledge of the complex ASFV, thus benefiting our understanding of the interplay between ASFV infection and the host's inflammatory responses.IMPORTANCEAfrican swine fever (ASF) is a devastating viral disease in pigs, and excessive inflammatory responses induced by ASFV mainly cause death. Thus, the study of the proinflammatory virulent proteins and the detailed mechanisms are important to ASF control. Here, I177L was demonstrated to be an essential protein in ASFV-mediated inflammation, which performs by simultaneously activating the NF-κB signaling and the NLRP3 inflammasome. The finding elucidates the molecular mechanism underlying ASFV-activated inflammatory responses for the first time. It provides a theoretical foundation for reducing the high mortality caused by excessive inflammation and opens new avenues for small-molecule drug development and vaccine design targeting ASFV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0208024"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710468","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}