Journal of Virology最新文献

{"title":"Seneca Valley virus infection exploits DNA damage response to facilitate viral replication.","authors":"Jiangwei Song, Zijian Li, Jingjing Yang, Ruiyi Ma, Dan Wang, Rong Quan, Xuexia Wen, Jue Liu","doi":"10.1128/jvi.02211-24","DOIUrl":"10.1128/jvi.02211-24","url":null,"abstract":"<p><p>Seneca Valley virus (SVV) is an emerging pathogen that causes severe vesicular diseases in swine, posing a significant threat to the global pork industry. DNA and RNA viruses manipulate the host DNA damage response (DDR) to modulate cellular machinery and facilitate their life cycles. However, the interaction between the host DDR and SVV infection remains unexplored. Here, we aimed to comprehensively investigate the DDR and DNA repair signaling pathways during SVV infection. We found that SVV infection causes DNA damage and triggers distinct DDR signaling pathways, including ataxia telangiectasia-mutated (ATM) kinase, ATM-Rad3-related kinase, and DNA-dependent protein kinase. However, it failed to induce the formation of γH2AX and 53BP1 foci, resulting in unrepaired DNA damage. Furthermore, we found that SVV 2B and 2C proteins can activate DDR signaling pathways and impair DNA repair. SVV-induced DDR triggered NF-κB signaling accompanied by upregulation of pro-inflammatory cytokines, as evidenced by the inhibition of ATM kinase, abolished SVV-induced NF-κB activation. Inhibition of the ATM pathway attenuated SVV replication. These findings expand our understanding of host DDR manipulation during viral infection and provide crucial insights into a novel mechanism exploited by SVV to regulate the inflammatory response for efficient replication.IMPORTANCEDDR is a cellular machinery that senses and repairs host DNA lesions to maintain genome integrity. Viruses have evolved diverse strategies to manipulate host DDR for replicative efficiency. SVV is an emerging virus that causes vesicular diseases in pigs and severely threatens the swine industry. However, the interaction between SVV and DDR remains unclear. Here, we found that SVV modulates host DDR pathways to facilitate viral replication. Our results demonstrated that SVV infection causes DNA damage, activates ATM-mediated DNA double-strand break response, and impedes DNA repair. SVV 2B and 2C proteins induced DNA damage and activated the DDR pathway while impairing repair mechanisms. This study revealed a fine-tuned molecular mechanism of SVV-modulated DDR that contributes to viral replication, facilitating deeper insight into SVV replication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0221124"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Japanese encephalitis virus NS1 protein concentrates ER membranes in a cytoskeleton-independent manner to facilitate viral replication.","authors":"Shengda Xie, Xinxin Lin, Qing Yang, Miaolei Shi, Xingmiao Yang, Ziyu Cao, Ruibing Cao","doi":"10.1128/jvi.02113-24","DOIUrl":"10.1128/jvi.02113-24","url":null,"abstract":"<p><p>Orthoflaviviruses remodel the endoplasmic reticulum (ER) network to construct replication organelles (ROs) for RNA replication. In this study, we demonstrate that the Japanese encephalitis virus (JEV) NS1 protein concentrates ER membranes in the perinuclear region, which provides a substantial membrane source for viral replication. Subsequently, the virus forms main replication organelles within this membrane-concentrated area to facilitate efficient replication. This process relies on the ER localization signal, glycosylation, dimerization, and membrane-binding sites of the NS1 protein. In conclusion, our study highlights the role of the NS1 protein in the formation of the ROs by JEV, providing new insights into orthoflavivirus replication.IMPORTANCEOrthoflaviviruses use the endoplasmic reticulum (ER) membranes for replication by forming invaginations to assemble the replication organelles. Here, we found that Japanese encephalitis virus (JEV) utilizes the NS1 protein to concentrate a significant number of ER membranes in the perinuclear area, thereby providing a membrane source for viral replication and facilitating the formation of main replication organelles (MROs). This process depends on the ER localization signals of NS1, as well as its glycosylation, dimerization, and membrane-binding sites, but not on the cytoskeleton. In summary, our study highlights how NS1 remodels ER membranes to facilitate the formation of MROs for JEV, thereby accelerating viral replication.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0211324"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Herpes simplex virus assembly and spread in murine skin after infection from the outside.","authors":"Timmy Richardo, Xiaokun Liu, Katinka Döhner, Tsung-Yu Chao, Anna Buch, Anne Binz, Anja Pohlmann, Madeleine de le Roi, Wolfgang Baumgärtner, Korbinian Brand, Rudolf Bauerfeind, Reinhold Förster, Beate Sodeik, Stephan Halle","doi":"10.1128/jvi.01638-24","DOIUrl":"10.1128/jvi.01638-24","url":null,"abstract":"<p><p>Herpes simplex viruses (HSV) cause many skin diseases, particularly in immunocompromised patients. HSV-1 infection of murine skin recapitulates many aspects of human pathology. However, many protocols rely on mechanical or enzymatic skin disruption to induce lesions, although this can alter skin homeostasis and prime antiviral inflammation before inoculation. To investigate the initial events following HSV-1 primary skin infection before the onset of symptoms, we developed a novel murine <i>ex vivo</i> explant model using gentle depilation without further scarification and infected keratinocytes from the outside with minimal tissue damage. Two-photon microscopy showed that HSV-1 spread exclusively in the epidermis. The infection centers increased in number and size over time and contained hundreds of infected keratinocytes. We investigated the HSV-1 spread at the cellular level, using reporter strains with fluorescently tagged capsid protein VP26, and observed the formation of nuclear capsid assembly sites and nuclear capsid egress and the recruitment of the inner tegument protein pUL37GFP, the outer tegument protein VP11/12GFP, and the envelope protein gDGFP to cytoplasmic capsids. By using electron microscopy, the skin appeared intact, and keratinocytes contained many nuclear capsids, primary virions in the nuclear envelope, cytosolic membrane-associated capsids, and enveloped virions. Our protocol provides a robust and reproducible approach to investigate the very early events of HSV-1 spread in the skin, to characterize the phenotypes of HSV-1 mutants in terminally differentiated skin tissues, and to evaluate potentially antiviral small molecules in a preclinical <i>ex vivo</i> infection model.</p><p><strong>Importance: </strong>This study describes a novel murine <i>ex vivo</i> skin explant model to investigate early events in HSV-1 infection without causing significant tissue damage. To infect from the outside, via the apical keratinocytes, this method relies on gentle depilation, which maintains skin integrity. HSV-1 spread exclusively within the epidermis, with infection centers increasing over time and involving hundreds of keratinocytes. Using advanced microscopy techniques, we tracked HSV-1 spread at the cellular level and intracellular assembly of all intermediate virus structures. This model offers a valuable tool for studying the initial stages of HSV-1 infection, assessing viral mutant phenotypes, and testing antiviral compounds in a more physiological context to provide critical insights into HSV-1 pathogenesis and therapeutic strategies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0163824"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In situ</i> structures of the contractile nanomachine myophage Mu in both its extended and contracted states.","authors":"Junquan Zhou, Liwen Wang, Hao Xiao, Wenyuan Chen, Zhonghua Liu, Jingdong Song, Jing Zheng, Hongrong Liu","doi":"10.1128/jvi.02056-24","DOIUrl":"10.1128/jvi.02056-24","url":null,"abstract":"<p><p>Myophage Mu is a representative of contractile nanomachines with a simple tail baseplate. It has the capacity to infect a range of intestinal bacteria and has extensive applications in genetic engineering research. Nevertheless, a comprehensive understanding of the entire structure and contractile mechanisms of Mu remains elusive. Using cryo-electron microscopy (cryo-EM), we resolved the asymmetric structures of Mu in both its extended and contracted states, the latter of which lacked the tail baseplate, at near-atomic resolutions. We built the atomic models for the extended Mu, encompassing the head, the connector complex, the tail, and the simple baseplate. It is noteworthy that we identified the position and structure of the tail tube initiator protein gp43 (referred to as the DNA circularization protein). The protein gp43 plays a crucial role not only in the baseplate assembly and DNA circularization but also in stabilizing the wedge-hub connection and mediating tail contraction. Except for the baseplate structure, the structural comparison of Mu in its extended and contracted states revealed that only the tail sheath protein gp39 and the C-terminus of the tail terminator protein gp37 undergo notable conformational changes to accommodate the tail contraction, whereas the remaining protein components remained unchanged. Our structures exhibited conserved properties among the majority of myophages, thereby providing valuable insights into the contraction mechanisms across myophages and contractile injection systems (CISs).</p><p><strong>Importance: </strong>Despite extensive study, the asymmetric structures of phage Mu, a highly effective transposable myophage, remain unknown. In this study, we present the high-resolution structures of Mu in both its extended and contracted states. The comparison of the two structures allows for the illustration of detailed conformational changes of the head-to-tail complex during the process of tail contraction. The contraction mechanism of Mu is highly conserved and widely adapted to all contractile nanomachines that share common structural features with Mu.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0205624"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between human immunodeficiency virus and human endogenous retroviruses.","authors":"Mengying Li, Fengting Yu, Baoli Zhu, Jiang Xiao, Chang Yan, Xiaojie Yang, Xuelei Liang, Fang Wang, Hanxi Zhang, Fujie Zhang","doi":"10.1128/jvi.02319-24","DOIUrl":"10.1128/jvi.02319-24","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV), a retrovirus of the Lentivirus genus, targets CD4⁺ T cells, causing immune dysfunction and AIDS. Approximately 8% of the human genome consists of human endogenous retroviruses (HERVs), ancient retroviral remnants that may interact with HIV. Despite antiretroviral therapy, challenges such as drug resistance, poor immune reconstitution (PIR), and reservoirs remain. This GEM discusses the impact of HIV on HERVs, the potential roles of HERVs in PIR and reservoirs, and provides insights into future research directions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0231924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFI16 recruits HDAC1 and HDAC2 to deacetylate the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA), facilitating latency.","authors":"Anandita Ghosh, Jeffrey Britto, Bala Chandran, Arunava Roy","doi":"10.1128/jvi.01549-24","DOIUrl":"10.1128/jvi.01549-24","url":null,"abstract":"<p><p>IFI16 (interferon-γ-inducible protein 16) is an innate-immune DNA sensor that detects viral dsDNA in the nucleus. It also functions as an antiviral restriction factor, playing a crucial role in regulating the latency/lytic balance of several herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). We previously demonstrated that IFI16 achieves this by regulating the deposition of H3K9me3 marks on the KSHV genome. Here, we explored whether IFI16 impacts the KSHV latency/lytic balance through additional mechanisms. Our analysis of the IFI16 interactome revealed that IFI16 binds to the class-I HDACs, HDAC1 and HDAC2, and recruits them to the KSHV major latency protein, latency-associated nuclear antigen (LANA). Previous reports have suggested that LANA undergoes lysine acetylation through unknown mechanisms, which results in the loss of its ability to bind to the KSHV transactivator protein (RTA) promoter. However, how the LANA acetylation-deacetylation cycle is orchestrated and what effect this has on KSHV gene expression remains unknown. Here, we demonstrate that LANA, by default, undergoes post-translational acetylation, and during latency, IFI16 interacts with this acetylated LANA and recruits HDAC1/2 to it. This keeps LANA in a deacetylated form, competent in binding and repressing lytic promoters. However, during lytic reactivation, IFI16 is degraded via the proteasomal pathway, leading to the accumulation of acetylated LANA, which cannot bind to the RTA promoter. This results in the de-repression of the RTA and, subsequently, other lytic promoters, driving reactivation. These findings shed new light on the role of IFI16 in KSHV latency and suggest that KSHV utilizes the cellular IFI16-HDAC1/2 interaction to facilitate its latency.</p><p><strong>Importance: </strong>Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesviruses etiologically associated with several human malignancies, including Kaposi's sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman's disease. Understanding the molecular mechanisms governing the establishment and maintenance of latency in γ-herpesviruses is crucial because latency plays a pivotal role in oncogenesis and disease manifestation post-infection. Here, we have elucidated a new mechanism by which IFI16, a previously discovered antiviral restriction factor, is hijacked by KSHV to recruit class-I HDACs on latency-associated nuclear antigen (LANA), resulting in the latter's deacetylation. The acetylation status of LANA is critical for KSHV latency because it governs LANA's binding to the KSHV replication and transcription activator (RTA) promoter, an immediate-early gene crucial for lytic reactivation. Depletion of IFI16 results in the accumulation of acetylated LANA, which is incapable of maintaining latency. These newly discovered interactions between IFI16 and LANA and between IFI16 and HDAC1/2 enhance our understanding of KSHV latency regulations.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0154924"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of ubiquitin, cytoskeleton, and vesicular trafficking machinery in giant viruses.","authors":"Sangita Karki, Frank O Aylward","doi":"10.1128/jvi.01715-24","DOIUrl":"10.1128/jvi.01715-24","url":null,"abstract":"<p><p>Members of the phylum <i>Nucleocytoviricota</i>, which include \"giant viruses\" known for their large physical dimensions and genome lengths, are a diverse group of dsDNA viruses that infect a wide range of eukaryotic hosts. The genomes of nucleocytoviruses frequently encode eukaryotic signature proteins (ESPs) such as RNA- and DNA-processing proteins, vesicular trafficking factors, cytoskeletal components, and proteins involved in ubiquitin signaling. Despite the prevalence of these genes in many nucleocytoviruses, the timing and number of gene acquisitions remains unclear. While the presence of DNA- and RNA-processing proteins in nucleocytoviruses likely reflects ancient gene transfers, the origins and evolutionary history of other proteins are largely unknown. In this study, we examined the distribution and evolutionary history of a subset of viral-encoded ESPs (vESPs) that are widespread in nucleocytoviruses. Our results demonstrate that most vESPs involved in vesicular trafficking were acquired multiple times independently by nucleocytoviruses at different time points after the emergence of the eukaryotic supergroups, while viral proteins associated with cytoskeletal and ubiquitin system proteins exhibited a more complex evolutionary pattern exhibited by both shallow and deep branching viral clades. This pattern reveals a dynamic interplay between the co-evoluton of eukaryotes and their viruses, suggesting that the viral acquisition of many genes involved in cellular processes has occurred both through ancient and more recent horizontal gene transfers. The timing and frequency of these gene acquisitions may provide insight into their role and functional significance during viral infection.IMPORTANCEThis research is pertinent for understanding the evolution of nucleocytoviruses and their interactions with eukaryotic hosts. By investigating the distribution and evolutionary history of viral-encoded eukaryotic signature proteins, the study reveals gene transfer patterns, highlighting how viruses acquire genes that allow them to manipulate host cellular processes. Identifying the timing and frequency of gene acquisitions related to essential cellular functions provides insights into their roles during viral infections. This work expands our understanding of viral diversity and adaptability, contributing valuable knowledge to virology and evolutionary biology, while offering new perspectives on the relationship between viruses and their hosts.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0171524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracing more than two decades of Japanese encephalitis virus circulation in mainland China.","authors":"Gairu Li, Xinxin Li, Jie Chen, Phillipe Lemey, Bram Vrancken, Shuo Su, Simon Dellicour, Fabiana Gámbaro","doi":"10.1128/jvi.01575-24","DOIUrl":"10.1128/jvi.01575-24","url":null,"abstract":"<p><p>Japanese encephalitis is a viral disease caused by the Japanese encephalitis virus (JEV), primarily affecting rural areas of Asia and western Pacific region. China remains one of the main epicenters, experiencing a significant burden of human and animal cases despite vaccination efforts. The ecology of this arbovirus is complex, involving <i>Culex</i> mosquitoes as primary vectors, wading birds as natural reservoirs, and pigs as amplifying hosts. Given the virus's epidemiological importance in China, combined with the country's expanding pig farming industry and diverse climates, investigating the virus spread and its environmental drivers is needed to address its persistent burden. In this study, we conducted phylogeographic analyses by combining publicly available JEV envelope gene sequences from China and other regions. Our reconstructions revealed multiple introduction events leading to various circulating JEV clades in China, with one predominant clade. Additionally, our analyses showed a diffusion capacity of JEV exceeding previous estimates for co-circulating arboviruses. These differences could be attributed to pig trade or bird migration, calling for further investigations into the drivers of JEV spread.</p><p><strong>Importance: </strong>Japanese encephalitis virus (JEV) is the cause of Japanese encephalitis, a significant health concern in China. Despite being one of the most studied mosquito-borne viruses, no previous studies have combined genomic and geographic data to investigate the spatial epidemiology and dispersal capacity of the virus. In this study, we analyzed genomic, geographic, and environmental data to trace the dispersal history of JEV in China and explore the environmental factors influencing its distribution. Our findings show that JEV circulates predominantly in areas with higher temperatures, dense human and pig populations, and favorable conditions for <i>Culex</i> mosquitoes. Notably, our analyses showed a higher diffusion capacity of JEV compared to co-circulating viruses, possibly driven by factors like pig trade and bird migration. Our analysis calls for improved genomic surveillance and establishes a baseline for future studies on the effects of climate change, agricultural practices, and bird migration on JEV circulation.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0157524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLSCR1 suppresses SARS-CoV-2 infection by downregulating cell surface ACE2.","authors":"Ruiyi Ma, Xinyi Zhang, Ruonan Li, Xiaojing Dong, Wenjing Wang, Qi Jiang, Xia Xiao, Yujin Shi, Lan Chen, Tian Zheng, Zichun Xiang, Lili Ren, Zhuo Zhou, Xiaobo Lei, Jianwei Wang","doi":"10.1128/jvi.02085-24","DOIUrl":"10.1128/jvi.02085-24","url":null,"abstract":"<p><p>Type I interferons exert their antiviral effects against SARS-CoV-2 by inducing the expression of interferon-stimulated genes (ISGs), including but not limited to LY6E, CH25H, IFITM2/3, and IFIH1. However, the antiviral effect and underlying mechanisms of action of most ISGs in SARS-CoV-2 infection are not yet fully understood. By screening 109 ISG-knockout cell lines, we identify that phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein, acts as a crucial restriction factor against SARS-CoV-2 infection. Cells lacking PLSCR1 are highly susceptible to SARS-CoV-2 infection. Conversely, overexpression of PLSCR1 inhibits SARS-CoV-2 infection. Depletion of PLSCR1 enhances cellular entry of both pseudotyped and authentic SARS-CoV-2. Mechanistically, PLSCR1 inhibits SARS-CoV-2 entry by specifically downregulating plasma membrane expression of ACE2, the virus's receptor, without affecting the overall levels of ACE2 within the cell. As such, we unraveled previously unappreciated mechanisms by which PLSCR1 exerts its restrictive effect on SARS-CoV-2. These data provide new insights into the interplay between host innate antiviral immunity and SARS-CoV-2 and shed light on novel antiviral therapeutics.</p><p><strong>Importance: </strong>Phospholipid scramblase 1 (PLSCR1) has been identified as a critical host restriction factor against SARS-CoV-2 infection. In this study, we demonstrated that PLSCR1 inhibited SARS-CoV-2 entry by downregulating the plasma membrane expression of ACE2, the primary receptor for viral entry. Our findings elucidate a novel host-pathogen interaction that not only deepens our understanding of the innate immune response to SARS-CoV-2 but offers potential strategies for therapeutic interventions against COVID-19.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0208524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of RNA aptamers against chikungunya virus E2 envelope protein.","authors":"Kaku Goto, Ryo Amano, Akiko Ichinose, Akiya Michishita, Michiaki Hamada, Yoshikazu Nakamura, Masaki Takahashi","doi":"10.1128/jvi.02095-24","DOIUrl":"10.1128/jvi.02095-24","url":null,"abstract":"<p><p>Nucleic acid aptamers are a promising drug modality, whereas the generation of virus-neutralizing aptamers has remained difficult due to the lack of a robust system for targeting the viral particles of interest. Here, we took advantage of our latest platform technology of Systematic Evolution of Ligands by EXponential enrichment (SELEX) with virus-like particles (VLPs) and targeted chikungunya virus (CHIKV) as a model, the pathogenic reemerging virus with an unmet need for control. The identified aptamer against CHIKV-VLPs, Apt#1, and its truncated derivatives showed neutralizing activity with nanomolar IC50 values in a cell-based assay system using a pseudoviral particle of CHIKV (CHIKVpp). An antiviral-based chemical genetics approach revealed significant competition of Apt#1 with suramin, a reported interactant with domain A of the E2 envelope protein (E2DA), in both CHIKVpp and surface plasmon resonance (SPR) analyses, predicting E2DA to be the Apt#1 interface. In addition, Apt#1 interfered with the attachment of CHIKVpp, collectively suggesting its property as an attachment inhibitor via E2DA of CHIKV. Thus, the generation of the VLP-targeted aptamers proved to contribute to anti-CHIKV strategies and confirmed the utility of the platform as a novel and viable option for the development of neutralizing agents against viral particles of interest.IMPORTANCEOur latest SELEX technology using VLPs has generated aptamers that bind the native conformation of the incorporated envelope protein and achieve the virus binding and neutralizing effects. Indeed, the aptamer-probed target E2DA is a representative neutralization site on the surface of the viral particle, validating the utility of the VLP-driven procedure. Simultaneously, the enhanced antiviral effects of the aptamer in combination with approved drugs using the CHIKVpp assay with human cells indicated potential therapeutic strategies that are expected to help address unmet needs in CHIKV control. The robust affinity of the aptamer to viral particles demonstrated by SPR analysis can also lead to conjugates with antivirals as guiding molecules and aptasensors for diagnostic tools. Overall, our VLP-based method provided anti-CHIKV as well as a versatile platform applicable to other emerging and reemerging viruses, in preparation for outbreaks with the need for rapid development of antiviral strategies as next-generation theranostics.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0209524"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}