Journal of Virology最新文献

{"title":"Relative frequency dynamics and loading of beet necrotic yellow vein virus genomic RNAs during the acquisition by its vector <i>Polymyxa betae</i>.","authors":"Yi Guo, Mattia Dall'Ara, David Baldo, David Gilmer, Claudio Ratti","doi":"10.1128/jvi.01410-24","DOIUrl":"https://doi.org/10.1128/jvi.01410-24","url":null,"abstract":"<p><p>The beet necrotic yellow vein virus (BNYVV) is a multipartite virus with the highest number (up to five) of genomic segments among RNA viruses. Classified as a soil-borne virus, it is persistently transmitted by the protozoan <i>Polymyxa betae</i>. Previous studies have demonstrated that the relative frequency of the BNYVV genomic RNAs was modified depending on the host plant as well as the infected organ, resulting in distinct stoichiometric ratios between the viral RNAs. In this study, we investigate whether infection by the vector <i>P. betae</i> influences the relative abundance of BNYVV RNAs within the roots of the host plant <i>Beta vulgaris</i>. Furthermore, we examine the relative frequency of BNYVV genomic segments and the viral load of BNYVV at two different stages of <i>P. betae</i>'s biological cycle: zoospore and resting spore. Our finding offers new insights into understanding the biology of this soil-borne virus and its vector. Notably, the variations in the relative accumulation of BNYVV RNAs observed in zoospores and resting spores, along with a higher viral load in zoospores compared to resting spores, invite consideration of the virus's replicative capacity within the vector.</p><p><strong>Importance: </strong>Our understanding of the transmission of plant viruses by protozoan vectors remains poor and fragmented. The fate of viral elements in the living stages of the vector is unknown. Here, we first established a protocol allowing the purification of two forms of the vector free of cellular contaminants. This permitted the examination of the relative frequencies of beet necrotic yellow vein virus RNAs in the roots of its natural host and in two forms of its protozoan vector, <i>Polymyxa betae</i>, responsible for virus transmission. Our findings provide new insights into virus behavior during vector transmission, allowing us to analyze how the virus regulates its RNA frequencies and load within the vector. By focusing on the early stages of viral transmission and separating virus acquisition from transmission to new hosts, we pave the way for experiments aimed at elucidating the molecular mechanisms behind viral acquisition and the maintenance of viral genome integrity by <i>P. betae</i>.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0141024"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829177","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":"On professional mutualism: a blueprint for early-career virologists.","authors":"Priya S Shah","doi":"10.1128/jvi.01156-24","DOIUrl":"https://doi.org/10.1128/jvi.01156-24","url":null,"abstract":"<p><p>Are you an early-career virologist looking for an independent position? Are you searching for the right home for your lab and not sure what you are looking for? I am here to tell you that the right professional home may not be what you expected. The key is to find a home that offers professional mutualism-it allows you and your home department to grow in new directions and hopefully thrive in the process.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0115624"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829176","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 activation of complement C5a-C5aR1 axis in astrocytes facilitates the neuropathogenesis due to EV-A71 infection by upregulating CXCL1.","authors":"Peiyu Zhu, Wangquan Ji, Dong Li, Fang Wang, Tiantian Sun, Haiyan Yang, Shuaiyin Chen, Weiguo Zhang, Yuefei Jin, Guangcai Duan","doi":"10.1128/jvi.01514-24","DOIUrl":"https://doi.org/10.1128/jvi.01514-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Enterovirus A71 (EV-A71) is a common small RNA virus that is highly neuroinvasive. Emerging evidence indicates that the complement fragment C5a and its receptor C5aR1 are important drivers of neuroinflammation. However, the potential role of the C5a-C5aR1 axis in EV-A71 encephalitis remains largely elusive. Our previous studies revealed that EV-A71 can infect astrocytes and result in complement activation &lt;i&gt;in vivo&lt;/i&gt;. Here, we investigated how complement factors interact with astrocytes to promote a severe inflammatory response upon EV-A71 infection. Our data revealed that EV-A71 infected mainly astrocytes and caused astrocyte activation in the mouse brain, which was further verified in patients with EV-A71 infection and U87-MG cells. Notably, EV-A71 infection led to activation of the C5a-C5aR1 axis in U87-MG cells, and knockdown (siC5aR1) or blockade (PMX53) of C5aR1 significantly suppressed EV-A71-induced astrocyte activation and proinflammatory cytokine (e.g., CXCL1) production. Next, the activation of the C5a-C5aR1 axis in mouse astrocytes was confirmed. Compared with C5aR1 knockout mice, wild-type mice presented more severe symptoms and lower survival rates after EV-A71 infection. C5aR1 deficiency or blockade significantly reduced EV-A71-induced pathological damage and proinflammatory cytokine production in the mouse brain. Importantly, an increased level of soluble C5a was strongly correlated with the severity of symptoms in patients with EV-A71 infection. By using confocal microscopy, primary astrocytes, and human specimens, we observed that the increase in CXCL1 levels resulted mainly from astrocytes. Neutralizing CXCL1 significantly alleviated the neuropathological changes caused by EV-A71 infection, and the production of CXCL1 in astrocytes was regulated by p38 MAPK signaling. Taken together, our findings indicate that the activation of the C5a-C5aR1 axis in astrocytes facilitates the neuropathological changes resulting from EV-A71 infection, emphasizing the potential role of p38 MAPK-mediated CXCL1 production in these alterations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Enterovirus A71 (EV-A71) is a common small RNA virus with highly neuroinvasive tendencies. Our previous studies took the view that EV-A71 could infect astrocytes and result in complement activation &lt;i&gt;in vivo&lt;/i&gt;. We investigated how complement interacts with astrocytes to promote a severe inflammatory response upon EV-A71 infection in the study. As expected, our data demonstrate that EV-A71 triggers robust activation of the C5a-C5aR1 axis in astrocytes and that knockout or blockade of C5aR1 in animals exposed to lethal doses of EV-A71 significantly enhances survival by diminishing the production of the chemokines CXCL1 and IL-6. In addition, neutralizing CXCL1 significantly alleviates the neuropathogenesis caused by EV-A71 infection. Thus, inhibiting the C5a-C5aR1 axis has emerged as a potential therapeutic strategy to mitigate neural damage caused by EV-A71 infect","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0151424"},"PeriodicalIF":4.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829178","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":"Transcriptomic analysis of coxsackievirus B3 infection in induced pluripotent stem cell-derived brain-like endothelial cells.","authors":"Sarah F Hathcock, Julia Mamana, Taryn E Keyzer, Nadine Vollmuth, Mohammad-Reza Shokri, Henry D Mauser, Robert N Correll, Daryl W Lam, Brandon J Kim, Jon Sin","doi":"10.1128/jvi.01824-24","DOIUrl":"10.1128/jvi.01824-24","url":null,"abstract":"<p><p>Viral aseptic meningitis is a neuroinflammatory condition that occurs when viruses gain access to the central nervous system (CNS) and induce inflammation. The blood-brain barrier (BBB) is comprised of brain endothelial cells (BECs) that stringently regulate the passage of molecules, toxins, and pathogens from the circulation into the CNS. Through their unique properties, such as complex tight junctions, reduced rates of endocytosis, expression of efflux transporters, and restricted expression of leukocyte adhesion molecules, the BBB is often able to limit pathogen entry into the brain; however, certain neurotropic pathogens, such as coxsackievirus B3 (CVB3) are able to infect the CNS. We have previously demonstrated that CVB3 can infect and disrupt induced pluripotent stem cell-derived brain-like endothelial cells (iBECs), but the host response to this infection remains unknown. Here, we investigate global host transcriptional changes during CVB3 infection of iBECs using RNA sequencing. We validated our data set by exploring pathways altered by CVB3 using quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay of upregulated cytokines and interferon signaling molecules.</p><p><strong>Importance: </strong>Coxsackievirus B3 (CVB3) is a leading cause of viral aseptic meningitis that can produce severe disease in susceptible individuals. To gain access to the central nervous system, CVB3 must cross central nervous system barriers, such as the blood-brain barrier. Previously, we have shown that CVB3 infects a human stem cell-derived brain-like endothelial cell model. Here, we report the global transcriptome of stem cell-derived brain-like endothelial cells to CVB3 infection and provide proof-of-concept validation of the dataset using molecular biology techniques. These data could inform novel mechanisms of CVB3-mediated blood-brain barrier dysfunction.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0182424"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818411","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":"Aquatic circoviruses: emerging pathogens in global aquaculture - from discovery to disease management.","authors":"Yuanyuan Wang, Changjun Guo, Jianguo He","doi":"10.1128/jvi.01737-24","DOIUrl":"https://doi.org/10.1128/jvi.01737-24","url":null,"abstract":"<p><p>The expansion of global aquaculture has brought challenges from emerging pathogens, resulting in disease-related production losses across various regions. Among these pathogens, aquatic circoviruses-small, single-stranded DNA viruses initially detected in barbel (<i>Barbus barbus</i>)-have now been identified in multiple aquaculture species. These viruses have been associated with various clinical manifestations in economically important fish, crustacean, and mollusk species, including acute hemorrhage syndrome, which has shown mortality rates up to 95% in controlled laboratory infections of turbot. This review consolidates current knowledge on aquatic circoviruses, focusing on their genetic diversity, epidemiology, pathogenesis, and management strategies. The analysis encompasses observed host range patterns, documented instances of cross-species transmission, and evolutionary characteristics, such as host-specific clustering and recombination events. Research gaps are highlighted, particularly in understanding viral pathogenic mechanisms, host-pathogen interactions, and their ecological roles within aquatic ecosystems. We evaluate recent advances in diagnostic methods, including targeted vaccine design and RNA interference technology. The review outlines future research priorities, including elucidating cross-species transmission potential, developing effective treatments, and assessing the full economic impact of these viruses on aquaculture. By providing a comprehensive overview, this review aims to guide future research efforts and inform strategies to mitigate the impact of circoviruses on aquaculture sustainability.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0173724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818399","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":"FSTL1 and TLR4 interact with PEDV structural proteins to promote virus adsorption to host cells.","authors":"Chunyun Liu, Ning Kong, Hailong Liu, Yu Zhang, Wenzhen Qin, Wenli Zhao, Xinyu Yang, Yahe Wang, Xinyu Cao, Tian Liu, Yuchang Liu, He Sun, Wu Tong, Hai Yu, Hao Zheng, Daoliang Lan, Shengsong Xie, Guangzhi Tong, Tongling Shan","doi":"10.1128/jvi.01837-24","DOIUrl":"https://doi.org/10.1128/jvi.01837-24","url":null,"abstract":"<p><p>Infection with porcine epidemic diarrhea virus (PEDV) results in enormous economic damage to the global swine industry. PEDV starts its life cycle by binding to the receptors of host cells and adsorbing onto the cellular surfaces. However, it is still unknown how PEDV adsorbs onto the surface of host cells and the mechanism beneath the interplay of host cell transmembrane protein with PEDV proteins. FSTL1, which is a secreted glycoprotein, participates in diverse pathological and physiological processes, including immune modulation and cell proliferation and differentiation. The transmembrane protein, TLR4, serves as a pattern recognition receptor recognizing a broad spectrum of pathogens, which exerts a crucial effect on the host immune system. In this study, we identified that FSTL1 promoted PEDV infection. Further studies demonstrated the interactive relationship between FSTL1 and PEDV structural proteins (N and S2). In addition, we also confirmed that TLR4 interacted with FSTL1 and PEDV N, S1, and S2 proteins on the cell surface. Moreover, FSTL1 promoted the interaction of TLR4 and PEDV and induced viral adsorption to host cells. This study offers explicit evidence that FSTL1 and TLR4 act as mediators for host cell adsorption of PEDV by interacting with PEDV N/S proteins.IMPORTANCEAs a highly infectious porcine epidemic diarrhea virus (PEDV)-induced intestinal condition of swine, porcine epidemic diarrhea (PED) results in a 100% death rate among suckling piglets and poses a serious economic burden to global swine farming. Therefore, it is essential to investigate the mechanism of virus infection, replication, and proliferation. Virus begins its life cycle by binding to the receptor of host cells and adsorbing onto the cellular surfaces. However, it remains unclear how PEDV adsorbs onto the host cell surfaces. This study revealed that host protein FSTL1 interacted with the PEDV N and S2 proteins, while TLR4 interacted with the FSTL1 and PEDV proteins (N, S1, and S2). Moreover, we thoroughly and methodically demonstrated that FSTL1 was engaged in the PEDV internalization and attachment processes by promoting the recognition of PEDV NS proteins by TLR4 and induced the viral adsorption to host cells.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0183724"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818406","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 conserved cysteine in the DNA-binding domain of MmuPV1 E2 is required for replication <i>in vivo</i>.","authors":"Jessica Gonzalez, Kennedy Stoll, Marsha DeSmet, Elliot J Androphy","doi":"10.1128/jvi.01423-24","DOIUrl":"https://doi.org/10.1128/jvi.01423-24","url":null,"abstract":"<p><p>The papillomavirus (PV) E2 protein is highly conserved, consisting of an N-terminal transactivation domain linked to a C-terminal DNA binding and dimerization domain (DBD) by a flexible hinge region. The E2 DBD exhibits a helix-turn-helix structure that dimerizes into a beta barrel prior to binding DNA; the first helix, α1, is responsible for recognition of the palindromic E2 binding site. The DNA recognition helix consists of a tract of basic amino acids with a highly conserved central cysteine residue. Previous mutational analysis studies on this conserved cysteine have found that it is not required for viral replication or DNA binding. To investigate the function of this conserved cysteine <i>in vitro</i> and <i>in vivo</i>, we generated point mutations in MmuPV1 E2 at cysteine 307. We report here that this cysteine in the DNA recognition helix is required for transient viral replication and transactivation of proximal promoters, but C307 point mutants are still capable of enhancing the activation of distant upstream promoters <i>in vitro</i>. MmuPV1 genomes with the C307 mutation failed to produce warts when injected into mice, suggesting that the DNA recognition cysteine is required for viral replication <i>in vivo</i>.</p><p><strong>Importance: </strong>Papillomaviruses are the etiological agents of cancers of the oropharynx and anogenital tract. Understanding the mechanisms underlying PV pathogenesis is complicated by the strict species tropism displayed by the virus. The research presented here is significant because it links <i>in vitro</i> and <i>in vivo</i> models investigating the role of a conserved cysteine in the MmuPV1 E2 protein. This work elucidates the molecular mechanisms that regulate PV transcription and DNA replication and how these contribute to disease progression.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0142324"},"PeriodicalIF":4.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel lineage of anelloviruses with large genomes identified in dolphins.","authors":"Matthew D De Koch, Mart Krupovic, Russell Fielding, Kendal Smith, Kelsie Schiavone, Katharine R Hall, Vincent S Reid, Diallo Boyea, Emma L Smith, Kara Schmidlin, Rafaela S Fontenele, Eugene V Koonin, Darren P Martin, Simona Kraberger, Arvind Varsani","doi":"10.1128/jvi.01370-24","DOIUrl":"https://doi.org/10.1128/jvi.01370-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Anellovirus infections are ubiquitous in mammals but lack any clear disease association, suggesting a commensal virus-host relationship. Although anelloviruses have been identified in numerous mammalian hosts, their presence in members of the family Delphinidae has yet to be reported. Here, using a metagenomic approach, we characterize complete anellovirus genomes (&lt;i&gt;n&lt;/i&gt; = 69) from four Delphinidae host species: short-finned pilot whale (&lt;i&gt;Globicephala macrorhynchus&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 19), killer whale (&lt;i&gt;Orcinus orca&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 9), false killer whale (&lt;i&gt;Pseudorca crassidens&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 6), and pantropical spotted dolphin (&lt;i&gt;Steno attenuatus&lt;/i&gt;, &lt;i&gt;n&lt;/i&gt; = 1). Sequence comparison of the open reading frame 1 (ORF1) encoding the capsid protein, the only conserved gene shared by all anelloviruses, shows that the Delphinidae anelloviruses form a novel genus-level clade that encompasses 22 unique species-level groupings. We provide evidence that different Delphinidae species can be co-infected by multiple anelloviruses belonging to distinct species groupings. Notably, the ORF1 protein of the Delphinidae anelloviruses is considerably larger than those encoded by all previously described anelloviruses from other hosts (spanning 14 vertebrate orders and including 27 families). Comprehensive analysis of the ORF1 sequences and predicted protein structures showed that the increased size of these proteins results from divergent elaborations within the capsid-distal P2 subdomain and elongation of the C-terminal domain of ORF1. Comparative structural and phylogenetic analyses suggest that acquisition of the P2 subdomain and its diversification occurred convergently in the anelloviruses associated with primate and Delphinidae hosts. Collectively, our results further the appreciation of diversity and evolution of the ubiquitous and enigmatic viruses in the family &lt;i&gt;Anelloviridae&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Anelloviruses are ubiquitous in mammals, but their infection has not yet been linked to any disease, suggesting a commensal virus-host relationship. Here, we describe the first anelloviruses associated with diverse species of dolphins. The dolphinid anelloviruses represent a new genus (tentatively named \"Qoptorquevirus\") and encode open reading frame 1 (ORF1) (capsid) proteins that are considerably larger than those encoded by previously described anelloviruses from other hosts. Comprehensive analysis of the ORF1 sequences and predicted protein structures revealed the underlying structural basis for such an extravagant ORF1 size and suggested that ORF1 size increased convergently in the anelloviruses associated with primate and Delphinidae hosts, respectively. Collectively, our results provide insights into the diversity and evolution of &lt;i&gt;Anelloviridae&lt;/i&gt;. Further exploration of the anellovirus diversity, especially in the host species that have not yet been sampled, is expected to further clarify their evolutionary trajecto","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0137024"},"PeriodicalIF":4.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel replication-competent reporter-expressing Rift Valley fever viruses for molecular studies.","authors":"Aitor Nogales, Celia Alonso, Sandra Moreno, Gema Lorenzo, Belén Borrego, Luis Martinez-Sobrido, Alejandro Brun","doi":"10.1128/jvi.01782-24","DOIUrl":"https://doi.org/10.1128/jvi.01782-24","url":null,"abstract":"<p><p>Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic disease that causes severe disease in both domestic and wild ungulates and humans, making it a significant threat to livestock and public health. The RVFV genome consists of three single-stranded, negative-sense RNA segments differing in size: small (S), medium (M), and large (L). Segment S encodes the virus nucleoprotein N and the virulence-associated factor non-structural (NSs) protein in opposite orientations, separated by an intergenic region (IGR). To overcome the current need to use secondary techniques to detect the presence of RVFV in infected cells, we used T7-driven polymerase plasmid-based reverse genetics to generate replication-competent recombinant (r)RVFV expressing Nanoluciferase (Nluc) or Venus fluorescent proteins. These reporter genes were used as valid surrogates to track the presence of RVFV in mammalian and insect cells. Notably, we explored the genome plasticity of RVFV and compared four different strategies by modifying the viral segment S to introduce the reporter gene foreign sequences. The reporter-expressing rRVFV were stable and able to replicate in cultured mammalian and insect cells, although to a lesser extent than the recombinant wild-type (WT) counterpart. Moreover, rRVFV-expressing reporter genes were validated to identify neutralizing antibodies or compounds with antiviral activity. <i>In vivo</i>, all mice infected with the reporter-expressing rRVFV displayed an attenuated phenotype, although at different levels. These rRVFV-expressing reporter genes provide a novel approach to better understand the biology and pathogenesis of RVFV and represent an excellent biotechnological tool for developing new therapeutics against RVFV infections.</p><p><strong>Importance: </strong>Rift Valley fever virus (RVFV) is a mosquito-borne virus and zoonotic agent threat that can be deadly to domestic or wild ungulates, and humans. In this work, we used reverse genetics approaches to explore the genome plasticity of RVFV by generating a set of recombinant (r)RVFV that express fluorescent or luminescent proteins to track viral infection. All the generated reporter-expressing rRVFVs were able to propagate in mammalian or insect cells and a mouse model of infection. Our studies may contribute to advances in research on RVFV and other bunyaviruses and pave the way for the development of novel vaccines and the identification of new antivirals for the prophylactic and therapeutic treatment, respectively, of RVFV infections.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0178224"},"PeriodicalIF":4.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813681","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":"Equine lentivirus Gag protein degrades mitochondrial antiviral signaling protein via the E3 ubiquitin ligase Smurf1.","authors":"Kewei Chen, Bingqian Zhou, Xinhui Wang, Guangpu Yang, Yuezhi Lin, Xuefeng Wang, Cheng Du, Xiaojun Wang","doi":"10.1128/jvi.01691-24","DOIUrl":"https://doi.org/10.1128/jvi.01691-24","url":null,"abstract":"<p><p>Equine infectious anemia virus (EIAV) and HIV-1 are both members of the <i>Lentivirus</i> genus and are similar in virological characters. EIAV is of great concern in the equine industry. Lentiviruses establish a complex interaction with the host cell to counteract the antiviral responses. There are various pattern recognition receptors in the host, for instance, the cytosolic RNA helicases interact with viral RNA to activate the mitochondrial antiviral signaling protein (MAVS) and subsequent interferon (IFN) response. However, viruses also exploit multiple strategies to resist host immunity by targeting MAVS, but the mechanism by which lentiviruses are able to target MAVS has remained unclear. In this study, we found that EIAV infection induced MAVS degradation, and that EIAV Gag protein recruited the E3 ubiquitin ligase Smurf1 to polyubiquitinate and degrade MAVS. The CARD domain of MAVS and the WW domain of Smurf1 are responsible for the interaction with Gag. EIAV Gag is a precursor polyprotein of the membrane-interacting matrix p15, the capsid p26, and the RNA-binding nucleocapsid proteins p11 and p9. Therefore, we analyzed which protein domain of Gag could interact with MAVS and Smurf1. We found that p15 and p26, but not p11 or p9, target MAVS for degradation. Moreover, we identified the key amino acid residues that support the interactions between p15 or p26 and MAVS or Smurf1. The present study describes a novel role of the EIAV structural protein Gag in targeting MAVS to counteract innate immunity, and reveals the mechanism by which the equine lentivirus can antagonize against MAVS.IMPORTANCEHost anti-RNA virus innate immunity relies mainly on the recognition by retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), and subsequently initiates downstream signaling through interaction with mitochondrial antiviral signaling protein (MAVS). However, viruses have developed various strategies to counteract MAVS-mediated signaling, although the method of antagonism of MAVS by lentiviruses is still unknown. In this article, we demonstrate that the precursor (Pr55gag) polyprotein of EIAV and its protein domains p15 and p26 target MAVS for ubiquitin-mediated degradation through E3 ubiquitin ligase Smurf1. MAVS degradation leads to the inhibition of the downstream IFN-β pathway. This is the first time that lentiviral structural protein has been found to have antagonistic effects on MAVS pathway. Overall, our study reveals a novel mechanism by which equine lentiviruses can evade host innate immunity, and provides insight into potential therapeutic strategies for the control of lentivirus infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0169124"},"PeriodicalIF":4.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813677","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}