Journal of Virology最新文献

{"title":"Targeting USP22 to promote K63-linked ubiquitination and degradation of SARS-CoV-2 nucleocapsid protein.","authors":"Xin Xiao, Shifeng Li, Zhijin Zheng, Yingying Ji, Qian Du, Yibo Zuo, Ying Miao, Yukang Yuan, Hui Zheng, Fang Huang, Jun Wang","doi":"10.1128/jvi.02234-24","DOIUrl":"https://doi.org/10.1128/jvi.02234-24","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generally hijacks the cellular machinery of host cells for survival. However, how SARS-CoV-2 employs the host's deubiquitinase to facilitate virus replication remains largely unknown. In this study, we identified the host deubiquitinase USP22 as a crucial regulator of the expression of SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 NP), which is essential for SARS-CoV-2 replication. We demonstrated that SARS-CoV-2 NP proteins undergo ubiquitination-dependent degradation in host cells, while USP22 interacts with SARS-CoV-2 NP and downregulates K63-linked polyubiquitination of SARS-CoV-2 NP, thereby protecting SARS-CoV-2 NP from degradation. Importantly, we further revealed that sulbactam, an antibiotic, can reduce USP22 protein levels, eventually promoting the degradation of SARS-CoV-2 NP <i>in vitro</i> and <i>in vivo</i>. This study reveals the mechanism by which SARS-CoV-2-encoded NP protein employs host deubiquitinase for virus survival and provides a potential strategy to fight against SARS-CoV-2 infection.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (SARS-CoV-2 NP) plays a pivotal role in viral infection by binding to viral RNA, stabilizing the viral genome, and promoting replication. However, the interactions between SARS-CoV-2 NP and host intracellular proteins had not been elucidated. In this study, we provide evidence that SARS-CoV-2 NP interacts with the deubiquitinase USP22 in host cells, which downregulates SARS-CoV-2 NP ubiquitination. This reduction in ubiquitination effectively prevents intracellular degradation of SARS-CoV-2 NP, thereby enhancing its stability, marking USP22 as a potential target for antiviral strategies. Additionally, our findings indicate that sulbactam significantly decreases the protein levels of USP22, thereby reducing SARS-CoV-2 NP levels. This discovery suggests a novel therapeutic pathway in which sulbactam could be repurposed as an antiviral agent, demonstrating how certain antibiotics might contribute to antiviral treatment. This work thus opens avenues for drug repurposing and highlights the therapeutic potential of targeting host pathways to inhibit viral replication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0223424"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780120","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":"Synergistic effects of PA (S184N) and PB2 (E627K) mutations on the increased pathogenicity of H3N2 canine influenza virus infections in mice and dogs.","authors":"Xiangyu Xiao, Xinrui Wang, Fengpei Xu, Yanting Liang, Yi Luo, Shoujun Li, Pei Zhou","doi":"10.1128/jvi.01984-24","DOIUrl":"https://doi.org/10.1128/jvi.01984-24","url":null,"abstract":"<p><p>As companion animals, dogs are susceptible to various subtypes of influenza A virus (IAV), with the H3N2 and H3N8 subtypes of canine influenza virus (CIV) stably circulating among canines. Compared to the H3N8 CIV, the H3N2 CIV is more widely prevalent in canine populations and demonstrates increased adaptability to mammals, potentially facilitating cross-species transmission. Therefore, a comprehensive elucidation of the mechanisms underlying H3N2 CIV adaptation to mammals is imperative. In this study, we serially passaged the GD14-WT strain in murine lungs, successfully establishing a lethal H3N2 CIV infection model. From this model, we isolated the lethal strain GD14-MA and identified the key lethal mutations PA(S184N) and PB2(E627K). Moreover, the GD14-ma[PA(S184N)+PB2(E627K)] strain exhibited markedly enhanced pathogenicity in dogs. Viral titers in lung tissues from infected dogs and mice showed that GD14-ma[PA(S184N)+PB2(E627K)] does not increase its pathogenicity to mice and dogs by upregulating viral titers compared to the GD14-WT strain. Notably, sequence alignments across all H3N2 IAVs showed an increasing prevalence of the PA (S184N) and PB2 (E627K) mutations from avian to human hosts. Finally, single-cell RNA sequencing of infected mouse lung tissues showed that GD14-ma[PA(S184N)+PB2(E627K)] effectively evaded host antiviral responses, inducing a robust inflammatory reaction. Considering the recognized role of the PB2 (E627K) mutation in the mammalian adaptation of IAVs, our findings underscore the importance of ongoing surveillance for the PA (S184N) mutation in H3N2 IAVs.IMPORTANCESince the 21st century, zoonotic viruses have frequently crossed species barriers, posing significant global public health challenges. Dogs are susceptible to various influenza A viruses (IAVs), particularly the H3N2 canine influenza virus (CIV), which has stably circulated and evolved to enhance its adaptability to mammals, including an increased affinity for the human-like SAα2,6-Gal receptor, posing a potential public health threat. Here, we simulated H3N2 CIV adaptation in mice, revealed that the synergistic PA(S184N) and PB2(E627K) mutations augment H3N2 CIV pathogenicity in dogs and mice, and elucidated the underlying mechanisms at the single-cell level. Our study provides molecular evidence for adapting the H3N2 CIV to mammals and underscores the importance of vigilant monitoring of genetic variations in H3N2 CIV.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0198424"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780200","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":"Bispecific antibodies targeting MPXV A29 and B6 demonstrate efficacy against MPXV infection.","authors":"Mengjun Li, Jiayin Chen, Fungxiang Wang, Jiahua Kuang, Yun Peng, Sadia Asghar, Wei Zhao, Yang Yang, Chenguang Shen","doi":"10.1128/jvi.02320-24","DOIUrl":"https://doi.org/10.1128/jvi.02320-24","url":null,"abstract":"<p><p>Recently, the monkeypox virus (MPXV) outbreak was once again declared by the World Health Organization as a global health emergency, and currently, there is no specific drug against MPXV. During the replication cycle, MPXV produces two distinct forms of viral particles: extracellular enveloped virus (EEV), released via exocytosis, and intracellular mature virus (IMV), expelled through host cell lysis. A29 and B6 proteins are membrane proteins found on the IMV and EEV viral particles, respectively. This study designed two different bispecific antibodies (bsAbs) targeting specific antigens of the MPXV: the developed bsAb 9F8-3A1 targets two non-competitive binding epitopes on the MPXV protein A29, while bsAb 9F8-7C9 targets different antigen-binding epitopes on both A29 and B6. The <i>in vitro</i> and <i>in vivo</i> characterization assays demonstrated that the bsAbs provided complete protection against three poxvirus strains: vaccinia virus (VACV) Tiantan, VACV Western Reserve (VACV WR), and MPXV, surpassing the efficacy of all the parental monoclonal antibodies. Notably, the bsAb 9F8-7C9 exhibited the most effective antiviral activity. <i>In vivo</i> pharmacokinetic experiments showed that these two bsAbs have long half-lives in rhesus macaques. In conclusion, this study successfully developed two bispecific antibodies that target different epitopes, providing crucial insights for the development of decent antiviral drugs against MPXV and other orthopoxviruses.IMPORTANCEMpox is a viral zoonotic disease caused by MPXV infection. Since 2022, cases of mpox have been reported in non-endemic countries. The number of infections and deaths continues to rise, posing a serious threat to global health and safety. Currently, there are no specific treatments for mpox, making the development of effective therapeutic options urgent. In recent years, antibody-based drugs have been extensively studied for the treatment of various significant human viruses. However, there is a lack of research on therapeutic monoclonal antibodies for mpox, particularly in the development and application of bsAbs. In this context, we have designed effective bsAbs that demonstrate high antiviral activity both <i>in vitro</i> and <i>in vivo</i>. This research provides a theoretical foundation for the development of specific therapeutic agents for mpox and offers new approaches for clinical treatment, which is crucial for controlling the current outbreak.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0232024"},"PeriodicalIF":4.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772669","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":"Type II grass carp reovirus utilizes autophagosomes for viroplasm formation and subclinical persistent infection.","authors":"Qian Wang, Zichao Peng, Pengfei Chu, Bin Gui, Yongming Li, Lanjie Liao, Zuoyan Zhu, Fei Ke, Yaping Wang, Libo He","doi":"10.1128/jvi.00352-25","DOIUrl":"https://doi.org/10.1128/jvi.00352-25","url":null,"abstract":"<p><p>Grass carp reovirus (GCRV) is the most virulent pathogen within the genus <i>Aquareovirus</i>, belonging to the family <i>Spinareoviridae</i>. GCRV is categorized into three genotypes, with type II (GCRV-II) being the predominant strain circulating in China. Reoviruses are known to replicate and assemble in cytoplasmic inclusion bodies termed viroplasms; however, information regarding the formation of GCRV-II viroplasms and their specific roles in virus infection remains largely unknown. In this study, we investigated the formation and characteristics of viroplasms during GCRV-II infection. Immunofluorescence and confocal microscopy indicate that GCRV-II infection induces the formation of viroplasms, with the nonstructural protein NS79 being the key protein responsible for this process. Live-cell imaging and fluorescence recovery after photobleaching assays reveal that GCRV-II viroplasms lack liquid-like properties. Transmission electron microscopy confirms that GCRV-II viroplasms are membranous structures. Notably, we demonstrate that GCRV-II infection induces autophagy and the formation of autophagosomes and that GCRV-II utilizes these autophagosomes for viroplasm formation and virion assembly. Furthermore, we found that GCRV-II uses autophagosomes to evade the host immune system, establishing subclinical persistent infection. GCRV-II also employs autophagosomes for nonlytic release and viral spread. Collectively, these findings highlight distinctive characteristics of GCRV-II viroplasms compared to those of other animal reoviruses, offering valuable insights for the prevention and control of this virus.IMPORTANCEGrass carp reovirus (GCRV) is categorized into three genotypes, with GCRV-II being the most prevalent in China. Despite reoviruses being known for their replication and assembly in viroplasms, the specifics of GCRV-II viroplasm formation and its role in infection were unclear. Our study demonstrates that GCRV-II infection triggers the formation of viroplasms, primarily mediated by the nonstructural protein NS79. GCRV-II viroplasms are membranous structures that lack liquid-like properties, which are significantly different from the viroplasms of other reoviruses. Notably, our research unveils that GCRV-II infection induces autophagy and utilizes autophagosomes for viroplasm formation and virion assembly. Furthermore, we also confirm that GCRV-II utilizes autophagosomes for subclinical persistent infection, nonlytic release, and viral spread. Our results indicate that GCRV-II hijacks autophagosomes to form viroplasms and complete its life cycle. The characteristics of GCRV-II are significantly different from those of other animal reoviruses, providing important information for prevention and control of this virus.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0035225"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764028","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":"Proteogenomic analysis of Cyprinid herpesvirus 2 using high-resolution mass spectrometry.","authors":"Chen Xu, Fangxing Yu, Mingyang Xue, Zhenyu Huang, Nan Jiang, Yiqun Li, Yan Meng, Wenzhi Liu, Ya Zheng, Yuding Fan, Yong Zhou","doi":"10.1128/jvi.01960-24","DOIUrl":"https://doi.org/10.1128/jvi.01960-24","url":null,"abstract":"<p><p>Cyprinid herpesvirus 2 (CyHV-2) is the main pathogen responsible for the development of herpesviral hematopoietic necrosis disease (HVHND) in crucian carp (<i>Carassius auratus</i>). The CyHV-2 genome encodes approximately 150 genes that are expressed in a well-defined manner during productive infection. However, CyHV-2 open reading frames (ORFs) are primarily derived from sequence and homology analyses, and most lack protein-level evidence to support their properties. In this study, we used high-resolution mass spectrometry followed by proteogenomic mapping to achieve genome re-annotation of CyHV-2. Based on our results, a total of 1,683 MS/MS spectra could be mapped to the CyHV-2 genome through six-frame translation, with 1,665 corresponding to 117 currently annotated protein-coding ORFs. Three of the remaining 18 peptides were mapped to the N-terminal extension region of known ORFs. However, 12 novel CyHV-2 ORFs, designated nORF1-12, were identified and characterized for the first time based on the remaining 15 peptides that could be mapped to previously unannotated regions of the viral genome. And the sequence differences of the novel phosphorylated nORF1, also referred to as ORF25E, in different CyHV-2 strains indicated that the nORF1 is a prospective molecular marker that can monitor the evolution from the Japan (J) to the China (C) genotype of CyHV-2. These findings further validate existing annotations, expand the genomic landscape of CyHV-2, and provide a rich resource for aquatic virology research.IMPORTANCECyHV-2 is a viral pathogen that poses a significant threat to crucian carp farming. CyHV-2 has a large genome with complex sequence features and diverse coding mechanisms, which complicates accurate genome annotation in the absence of protein-level evidence. Here, we employed various protein extraction and separation methods to increase viral protein coverage and performed an integrated proteogenomic analysis to refine the CyHV-2 genome annotation. A total of 129 viral genes were confidently identified, including 117 currently annotated genes and 12 novel genes. For the first time, we present large-scale evidence of peptide presence and levels in the genome of aquatic viruses and confirm the majority of the predicted proteins in CyHV-2. Our findings enhance the understanding of the CyHV-2 genome structure and provide valuable insights for future studies on CyHV-2 biology.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0196024"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763847","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 plant virus attenuates the Toll immune pathway by degradation of Pellino to facilitate viral infection in insect vectors.","authors":"Yu-Xiao Du, Yu-Hua Qi, Yan-Hua Lu, Bo-Xue Li, Yu-Juan He, Yan Zhang, Lin Lin, Chuan-Xi Zhang, Xiao-Wei Wang, Jian-Ping Chen, Gang Lu, Jun-Min Li","doi":"10.1128/jvi.00021-25","DOIUrl":"https://doi.org/10.1128/jvi.00021-25","url":null,"abstract":"<p><p>Many plant viruses are persistently transmitted by insect vectors. The viral antagonism of insect innate immune responses is a critical step in ensuring persistent viral infection. Recent studies have shown that the Toll immune pathway mediates the persistent and propagative transmission of rice stripe virus (RSV) in its insect vector (<i>Laodelphax striatellus</i>). However, whether other host factors are involved in the Toll pathway and how RSV counteracts the Toll immune response in <i>L. striatellus</i> remain unclear. Here, we reported that LsPellino also inhibited RSV infection in <i>L. striatellus</i> by interacting with LsTube and participating in the Toll immune pathway. In contrast, the viral nonstructural protein NS3 hijacked the suppressor of cytokine signaling 5 (LsSOCS5) to promote the degradation of LsPellino via the 26S proteasome pathway, thereby suppressing the Toll immune response. In summary, these findings demonstrate that RSV attenuates the Toll immune pathway by degradation of LsPellino to facilitate viral infection in insect vectors. Our research provides new insights into controlling the transmission of vector-borne viruses.</p><p><strong>Importance: </strong>Plant virus diseases pose a serious threat to global crop production. Nearly half of the known plant viruses are persistently transmitted by insect vectors, and these plant viruses must counteract various innate immune responses to maintain persistent infection. Here, we uncover a novel counter-defense mechanism against Toll antiviral defense. Our research showed that LsPellino exerts antiviral function by interacting with LsTube and participating in the Toll immune pathway. To counteract this immunity, a plant virus, rice stripe virus, attenuates the Toll immune pathway and promotes viral infection by using viral nonstructural protein NS3 to mediate the degradation of LsPellino in its insect vector, <i>Laodelphax striatellus</i>. This study not only contributes to a better understanding of the arms race between viruses and insect vectors but also provides a new perspective for controlling the transmission of plant viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0002125"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753486","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 spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice.","authors":"Eryn Blass, Alessandro Colarusso, Malika Aid, Rafael A Larocca, R Keith Reeves, Dan H Barouch","doi":"10.1128/jvi.00247-25","DOIUrl":"https://doi.org/10.1128/jvi.00247-25","url":null,"abstract":"<p><p>As the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to the inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits the understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity. We, therefore, utilized a mouse model to investigate the spatiotemporal evolution of the immune response within the first 24 hours following intramuscular adenovirus serotype 26 (Ad26) vector vaccination in tissues. We show that the Ad26 vaccine-elicited innate immune response commences by 1 hour and rapidly evolves in tissues and blood within the first 24 hours, as reflected by the detection of cytokines, chemokines, cellular responses, and transcriptomic pathways. Furthermore, serum levels of IL-6, MIG, MIP-1α, MIP-1β, and TNF-α at 6 hours post-vaccination correlated with the frequency of vaccine-elicited memory CD8⁺ T cell responses evaluated at 60 days post-vaccination in blood and tissues. Taken together, our data suggest that the immune response to Ad26 vector vaccination commences quickly in tissues by 1 hour and that events by as early as 6 hours post-vaccination can shape vaccine-elicited CD8⁺ T cell responses at later memory time points.IMPORTANCEPrior studies have largely concentrated on innate immune activation in peripheral blood following vaccination. In this study, we report the detailed spatial and temporal innate immune activation in tissues following Ad26 vaccination in mice. We observed rapid innate activation not only in peripheral blood but also in draining lymph nodes and at the site of inoculation. Our findings provide a more detailed picture of the host response to vaccination than previously reported.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0024725"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753491","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":"Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection.","authors":"Roshan Ghimire, Rakshya Shrestha, Radhika Amaradhi, Lin Liu, Sunil More, Thota Ganesh, Alexandra K Ford, Rudragouda Channappanavar","doi":"10.1128/jvi.01668-24","DOIUrl":"https://doi.org/10.1128/jvi.01668-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced impaired antiviral immunity and excessive inflammatory responses cause lethal pneumonia. However, the &lt;i&gt;in vivo&lt;/i&gt; roles of key pattern recognition receptors that elicit protective antiviral and fatal inflammatory responses, specifically in the lungs, are not well described. Coronaviruses possess single-stranded RNA genome that activates TLR7/8 to induce an antiviral interferon (IFN) and robust inflammatory cytokine response. Here, using wild-type and TLR7-deficient (TLR7&lt;sup&gt;-/-&lt;/sup&gt;) mice infected with mouse-adapted SARS-CoV-2 (MA-CoV-2), we examined the role of TLR7 in the lung antiviral and inflammatory response and severe pneumonia. We showed that TLR7 deficiency significantly increased lung virus loads and morbidity/mortality, which correlated with reduced levels of type I IFNs (&lt;i&gt;Ifna/b&lt;/i&gt;), type III IFNs (&lt;i&gt;Ifnl&lt;/i&gt;), and IFN-stimulated genes (ISGs) in the lungs. A detailed evaluation of MA-CoV-2-infected lungs revealed increased neutrophil accumulation and lung pathology in TLR7&lt;sup&gt;-/-&lt;/sup&gt; mice. We further showed that blocking type I IFN receptor (IFNAR) signaling enhanced SARS-CoV-2 replication in the lungs and caused severe lung pathology, leading to 100% mortality compared to infected control mice. Moreover, immunohistochemical assessment of the lungs revealed increased numbers of SARS-CoV-2 antigen-positive macrophages, pneumocytes, and bronchial epithelial cells in TLR7&lt;sup&gt;-/-&lt;/sup&gt; and IFNAR-deficient mice compared to control mice. In summary, we conclusively demonstrated that despite TLR7-induced robust lung inflammation, TLR7-induced IFN/ISG responses suppress lung virus replication and pathology and provide protection against SARS-CoV-2-induced fatal pneumonia. Additionally, given the similar disease outcomes in control, TLR7&lt;sup&gt;-/-&lt;/sup&gt;, and IFNAR-deficient MA-CoV-2-infected mice and coronavirus disease 2019 (COVID-19) patients, we propose that MA-CoV-2-infected mice constitute an excellent model for studying COVID-19.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is caused by a delicate balance between a strong antiviral and an exuberant inflammatory response. A robust antiviral immunity and regulated inflammation are protective, while a weak antiviral response and excessive inflammation are detrimental. However, the key host immune sensors that elicit protective antiviral and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge are poorly defined. Here, we examined the role of viral RNA-mediated TLR7 activation in the lung antiviral and inflammatory responses in SARS-CoV-2-infected mice. We demonstrate that TLR7 deficiency led to a high rate of morbidity and mortality, which correlated with an impaired antiviral interferon (IFN)-I/III response, enhanced lung virus replication, and severe lung pathology. Furthermore, we show that blocking IFN-I signaling using anti-IFN receptor antibody promo","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0166824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753538","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":"Heat shock protein A1 inhibits the replication of foot-and-mouth disease virus by degrading viral RNA polymerase 3D through chaperone-mediated autophagy.","authors":"Mei Ren, Haiqian Zhou, Jin-En Wu, Jia-Ning Wang, Xuefei Wang, Sahibzada Waheed Abdullah, Huichen Guo, Shiqi Sun","doi":"10.1128/jvi.00168-25","DOIUrl":"https://doi.org/10.1128/jvi.00168-25","url":null,"abstract":"<p><p>Foot-and-mouth disease virus (FMDV), a member of the <i>Picornaviridae</i> family, is a single-stranded, positive-sense RNA virus. Heat shock protein A1 (HSPA1) has been shown to influence the entry, translation, assembly, and release of enterovirus A71 (EV-A71), another <i>Picornaviridae</i> family member. In this study, we demonstrate that HSPA1 plays a different role in the replication of FMDV. By investigating various stages of virus replication, we found that HSPA1 specifically inhibits the RNA replication stage in which HSPA1 inhibits viral RNA replication by degrading the viral RNA-dependent RNA polymerase (RdRp), 3D protein. In the presence of specific inhibitors, we find out that this degradation occurs through the autophagy pathway. Activation and blockage of chaperone-mediated autophagy (CMA) demonstrate that HSPA1 degrades 3D through the CMA pathway. Mutation analysis reveals that ₄₂₁QEKLI₄₂₅ is the key motif in 3D responsible for HSPA1-mediated CMA degradation. In summary, this study shows that HSPA1 can degrade the viral 3D protein through the CMA pathway, thereby inhibiting the RNA replication of FMDV and interfering with virus infection. This study, for the first time, demonstrates that HSPA1 employs its chaperone function to mediate the degradation of the FMDV RdRp, revealing the crucial role of HSPA1 in the FMDV infection process and suggesting that HSPA1 could be a potential target for the prevention and treatment of FMDV infection.</p><p><strong>Importance: </strong>Viral RNA replication is the key stage in understanding the pathogenic mechanisms of foot-and-mouth disease virus (FMDV). During this process, the viral non-structural protein 3D serves as an RNA-dependent RNA polymerase (RdRp) to synthesize progeny RNA using the viral genomic RNA as a template. However, the regulatory effect of host cells on FMDV 3D proteins has not yet been studied. In this study, we find that heat shock protein A1 (HSPA1) degrades the viral 3D protein through the chaperone-mediated autophagy (CMA) pathway, thereby inhibiting the RNA replication of FMDV and interfering with virus infection. This study, for the first time, demonstrates that HSPA1 employs its chaperone function to mediate the degradation of the FMDV RdRp.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0016825"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753441","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 ELF3-TRIM22-MAVS signaling axis regulates type I interferon and antiviral responses.","authors":"Qiaozhi Zhao, Pan Pan, Lirong Mo, Jiangtao Wu, Shengjie Liao, Hua Lu, Qiwei Zhang, Xiaoshen Zhang","doi":"10.1128/jvi.00004-25","DOIUrl":"https://doi.org/10.1128/jvi.00004-25","url":null,"abstract":"<p><p>Activation of the innate immune response is essential for host cells to restrict the dissemination of invading viruses and other pathogens. Proteins belonging to the tripartite motif (TRIM) family are key effectors in antiviral innate immunity. Among these, TRIM22, a RING-type E3 ubiquitin ligase, has been recognized as a significant regulator in the pathogenesis of various diseases. In the present study, we identified TRIM22 as a critical modulator of mitochondrial antiviral signaling protein (MAVS) activation. Loss of TRIM22 function led to reduced production of type I interferons (IFNs) in response to viral infection such as influenza A virus (IAV) or vesicular stomatitis virus (VSV), thereby facilitating viral replication. Mechanistically, TRIM22 was found to enhance retinoic acid-inducible gene I (RIG-I)-mediated signaling through the catalysis of Lys63-linked polyubiquitination of MAVS, which, in turn, activated the TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway, driving IFN-β production. Additionally, TRIM22 was shown to inhibit the assembly of the MAVS-NLRX1 inhibitory complex, further amplifying innate immune responses. Our findings also demonstrated that RNA virus infection upregulated TRIM22 expression via the nuclear translocation of ELF3, a transcription factor that activates TRIM22 gene expression. This regulatory loop underscores the role of TRIM22 in modulating the type I IFN pathway, providing critical insights into the host's antiviral defense mechanisms. Our research highlights the potential of targeting the ELF3-TRIM22-MAVS axis as a therapeutic strategy for enhancing antiviral immunity and preventing RNA virus infections.IMPORTANCEInterferon (IFN)-mediated antiviral responses are crucial for the host's defense against foreign pathogens and are regulated by various signaling pathways. The tripartite motif (TRIM) family, recognized for its multifaceted roles in immune regulation and antiviral defense, plays a significant part in this process. In our study, we explored the important role of TRIM22, a protein that helped regulate the host's immune response to viral infections. We found that TRIM22 enhances the Lys63-linked polyubiquitination of mitochondrial antiviral signaling protein (MAVS), which was essential for producing type I interferons. Interestingly, we discovered that the expression of TRIM22 increases after an RNA virus infection, due to a transcription factor ELF3, which moved into the nucleus of cells to activate TRIM22 transcription. This created a feedback loop that strengthens the role of TRIM22 in modulating the type I IFN pathway. By uncovering these mechanisms, we aimed to enhance our understanding of how the immune system works and provide insights that could lead to innovative antiviral therapies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0000425"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753581","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}