Laetitia Montacq, Doriana Flores, Hélène Giummarra, Laurane Pallandre, Anaïs Angot, Rodolphe Thomas, Amélie Charrier, Laurie Lamothe, Mélanie Lesne, Carine Bellet, Nicolas Keck, Françoise Pozet, Aurélien Tocqueville, Sophie Le Bouquin-Leneveu, Jésabel Laithier, Jean K Millet, Stéphane Bertagnoli, Marine Baud, Laurent Bigarré
{"title":"cds46, a highly variable carp edema virus gene.","authors":"Laetitia Montacq, Doriana Flores, Hélène Giummarra, Laurane Pallandre, Anaïs Angot, Rodolphe Thomas, Amélie Charrier, Laurie Lamothe, Mélanie Lesne, Carine Bellet, Nicolas Keck, Françoise Pozet, Aurélien Tocqueville, Sophie Le Bouquin-Leneveu, Jésabel Laithier, Jean K Millet, Stéphane Bertagnoli, Marine Baud, Laurent Bigarré","doi":"10.1099/jgv.0.002048","DOIUrl":"10.1099/jgv.0.002048","url":null,"abstract":"<p><p>Carp edema virus disease (CEVD) is a severe viral illness that causes substantial economic losses in wild and farmed common carp and koi. It is caused by carp edema virus (CEV), a member of the <i>Poxviridae</i> family<i>,</i> whose genetic diversity and genome evolution are poorly understood. Based on a genomic fragment of the <i>4a</i> gene, two genogroups, genogroup I (gI) and genogroup II (gII), have been identified in samples of different origins. By analysing a series of recent samples, we highlight here a new genomic region of interest that varies by substitutions, indels and putative recombinations. In the Japanese reference sequence, this region encodes an ORF, cds46, whose function is unknown despite weak homologies with genes of some members of the <i>Iridoviridae</i>. Surprisingly, AlphaFold protein structure prediction analyses link cds46-encoded ORF with cellular endonucleases, providing insights into its possible origin. The ORF is absent in all gI haplotypes and in some gII haplotypes. Apart from the absence of cds46, gI haplotypes show an insertion of 121 bp with no homology to any viral sequence. When present, cds46 showed two groups of alleles differentiated by substitutions. The analysis of the cds46 locus showed that some samples from fish batches contained mixes of different haplotypes, irrespective of their origin (i.e. France, Japan or Israel). In a 2023 sample, we also found a virus carrying a gII-like atypical <i>4a</i> allele first identified in France in 2015, indicating the limited but persistent spread of this virus in the country. The cds46 locus is a new target that may be useful for identifying and tracking CEV haplotypes.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William M de Souza, Charles H Calisher, Jean Paul Carrera, Holly R Hughes, Marcio R T Nunes, Brandy Russell, Natasha L Tilson-Lunel, Marietjie Venter, Han Xia
{"title":"ICTV Virus Taxonomy Profile: <i>Peribunyaviridae</i> 2024.","authors":"William M de Souza, Charles H Calisher, Jean Paul Carrera, Holly R Hughes, Marcio R T Nunes, Brandy Russell, Natasha L Tilson-Lunel, Marietjie Venter, Han Xia","doi":"10.1099/jgv.0.002034","DOIUrl":"https://doi.org/10.1099/jgv.0.002034","url":null,"abstract":"<p><p>Peribunyavirids produce enveloped virions with three negative-sense RNA segments comprising 10.7-12.5 kb in total. The family includes globally distributed viruses in multiple genera. While most peribunyavirids are maintained in geographically restricted vertebrate-arthropod transmission cycles, others are arthropod-specific or do not have a known vector. Arthropods can be persistently infected. Human and other vertebrate animal infections occur through blood feeding by an infected vector arthropod, resulting in diverse human and veterinary clinical outcomes in a strain-specific manner. Reassortment can occur between members of the same genus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family <i>Peribunyaviridae</i>, which is available at ictv.global/report/peribunyaviridae.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Singapore grouper iridovirus VP12 evades the host antiviral immune response by targeting the cGAS-STING signalling pathway.","authors":"Luhao Zhang, Linting Xu, Xin Zhang, Jiaming Liao, Shaozhu Kang, Siting Wu, Qiwei Qin, Jingguang Wei","doi":"10.1099/jgv.0.002031","DOIUrl":"10.1099/jgv.0.002031","url":null,"abstract":"<p><p>The emergence of Singapore grouper iridovirus (SGIV) has caused huge losses to grouper farming. SGIV is a DNA virus and belongs to the genus <i>Ranavirus</i>. Groupers infected with SGIV showed haemorrhaging and swelling of the spleen, with a mortality rate of more than 90% within a week. Therefore, it is of great significance to study the escape mechanism of SGIV from host innate immunity for the prevention and treatment of viral diseases in grouper. In this study, the viral proteins that interact with EccGAS were identified by mass spectrometry, and the SGIV VP12 protein that inhibits cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated antiviral innate immunity was screened by the dual-luciferase reporter gene assay. VP12 belongs to the late gene of the virus. The immunofluorescence analysis demonstrated that VP12 was aggregated and distributed in the cytoplasm during the early stage of virus infection and translocated into the nucleus at the late stage of virus infection. VP12 inhibited the activation of IFN3, ISRE and NF-κB promoter activities mediated by cGAS-STING, EcTBK1 and EcIRF3. Quantitative real-time PCR analysis showed that VP12 inhibited the expression of interferon-related genes, including those mediated by cGAS-STING. VP12 enhanced the inhibition of IFN3, ISRE and NF-κB promoter activity by EccGAS, EccGAS-mab-21 and EccGAS-delete-mab21. The interaction between VP12 and EccGAS was found to be domain independent. The immunoprecipitation results demonstrated that VP12 interacted and co-localized with EccGAS, EcTBK1 and EcIRF3. VP12 degraded the protein levels of EcTBK1 and EcIRF3 and degraded EcIRF3 through the protease pathway. These results suggest that SGIV VP12 protein escapes the cGAS-STING signalling pathway and degrades EcIRF3 protein expression through the protease pathway.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Panatda Saenkham-Huntsinger, Aleksandra K Drelich, Pinghan Huang, Bi-Hung Peng, Chien-Te K Tseng
{"title":"BALB/c mice challenged with SARS-CoV-2 B.1.351 β variant cause pathophysiological and neurological changes within the lungs and brains.","authors":"Panatda Saenkham-Huntsinger, Aleksandra K Drelich, Pinghan Huang, Bi-Hung Peng, Chien-Te K Tseng","doi":"10.1099/jgv.0.002039","DOIUrl":"10.1099/jgv.0.002039","url":null,"abstract":"<p><p>Up to one-third of individuals suffering from acute SARS-CoV-2 infection with the onset of severe-to-mild diseases could develop several symptoms of neurological disorders, which could last long after resolving the infection, known as neuro-COVID. Effective therapeutic treatments for neuro-COVID remain unavailable, in part, due to the absence of animal models for studying its underlying mechanisms and developing medical countermeasures against it. Here, we explored the impact of SARS-CoV-2 infection on the well-being of respiratory and neurological functions of BALB/c mice by using a clinical isolate of β-variant, i.e. B.1.351. We found that this β-variant of SARS-CoV-2 primarily infected the lungs, causing tissue damage, profound inflammatory responses, altered respiratory functions and transient but significant hypoxia. Although live progeny viruses could not be isolated, viral RNAs were detected across many anatomical regions of the brains in most challenged mice and triggered activation of genes encoding for NF<i>-kB</i>, <i>IL-6</i>, <i>IP-10</i> and <i>RANTES</i> and microglial cells. We noted that the significantly activated <i>IL-6</i>-encoded gene persisted at 4 weeks after infection. Together, these results suggest that this B.1.351/BALB/c model of SARS-CoV-2 infection warrants further studies to establish it as a desirable model for studies of neuropathogenesis and the development of effective therapeutics of neuro-COVID.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oropouche Virus: An Emerging Orthobunyavirus.","authors":"Natasha L Tilston-Lunel","doi":"10.1099/jgv.0.002027","DOIUrl":"10.1099/jgv.0.002027","url":null,"abstract":"<p><p>On 2 February 2024, the Pan American Health Organization/World Health Organization issued an epidemiological alert on rising Oropouche virus (OROV) infections in South America. By 3 August 2024, this alert level had escalated from medium to high. OROV has been a public health concern in Central and South America since its emergence in Brazil in the 1960s. However, the 2024 outbreak marks a turning point, with the sustained transmission in non-endemic regions of Brazil, local transmission in Cuba, two fatalities and several cases of vertical transmission. As of the end of August 2024, 9852 OROV cases have been confirmed. The 2024 OROV outbreak underscores critical gaps in our understanding of OROV pathogenesis and highlights the urgent need for antivirals and vaccines. This review aims to provide a concise overview of OROV, a neglected orthobunyavirus.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M A Macedo, T A Melgarejo, M Vasquez-Mayorga, M Cespedes, M R Rojas, T A Turini, O Batuman, W M Wintermantel, R L Gilbertson
{"title":"Squash vein yellowing virus from California emerged in the Middle East via intragenic and intergeneric recombination events in the hypervariable potyvirus P1 and ipomovirus P1a genes.","authors":"M A Macedo, T A Melgarejo, M Vasquez-Mayorga, M Cespedes, M R Rojas, T A Turini, O Batuman, W M Wintermantel, R L Gilbertson","doi":"10.1099/jgv.0.002033","DOIUrl":"10.1099/jgv.0.002033","url":null,"abstract":"<p><p>We present the complete sequence of the genomic RNA of an isolate of squash vein yellowing virus (<i>Ipomovirus cucurbitavenaflavi</i>) from California (SqVYV-CA) and show it is a recombinant virus with a highly divergent 5' UTR and proximal P1a gene. The evolution of SqVYV-CA involved an intrageneric event between unknown potyviruses, related to isolates of papaya ringspot virus (<i>Potyvirus papayanuli</i>) from the Old World, and an intergeneric event between this recombinant potyvirus (minor parent) and an isolate of SqVYV from Israel (SqVYV-IL) (major parent). These events occurred in mixed infections and in the potyvirus P1 and ipomovirus P1a recombination hotspots and resulted in SqVYV-CA having a potyvirus 5' UTR and chimeric P1-P1a gene/protein and the remainder of the genome from SqVYV-IL. The SqVYV-CA chimeric P1-P1a gene is under positive selection, and the protein is intrinsically disordered and may localize to the nucleus via nuclear localization signals in the P1 part. The C-terminal SqVYV-IL P1a part also diverged but retained the conserved serine protease motif. Furthermore, substantial divergence in SqVYV isolates from the Middle East was associated with genetic drift and a long evolutionary history in this region. The finding that the host range and symptomatology in cucurbits of SqVYV-CA is similar to those of SqVYV from Florida and SqVYV-IL, indicated that the recombinant part of the genome had no obvious effect on the virus-host interaction. A divergent part of the P1 sequence of the SqVYV-CA P1-P1a gene was used to develop a primer pair and RT-PCR test for specific detection of SqVYV-CA. This test was used to detect spread of SqVYV-CA to a new production area of California in 2021 and 2022. Together, these results demonstrate (i) a high level of genetic diversity exists among isolates of SqVYV and involved intra- and intergeneric recombination and genetic drift (mutation), (ii) evidence that SqVYV originated in the Middle East and that there were independent introductions into the New World and (iii) the remarkable genetic flexibility of the 5' proximal genes of these viruses.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Phylogeographic analysis of <i>Begomovirus</i> coat and replication-associated proteins.","authors":"Alvin Crespo-Bellido, J Steen Hoyer, Yeissette Burgos-Amengual, Siobain Duffy","doi":"10.1099/jgv.0.002037","DOIUrl":"https://doi.org/10.1099/jgv.0.002037","url":null,"abstract":"<p><p>Begomoviruses are globally distributed plant pathogens that significantly limit crop production. These viruses are traditionally described according to phylogeographic distribution and categorized into two groups: begomoviruses from the Africa, Asia, Europe and Oceania (AAEO) region and begomoviruses from the Americas. Monopartite begomoviruses are more common in the AAEO region, while bipartite viruses predominate in the Americas, where the begomoviruses lack the V2/AV2 gene involved in inter-cellular movement and RNA silencing suppression found in AAEO begomoviruses. While these features are generally accepted as lineage-defining, the number of known species has doubled due to sequence-based discovery since 2010. To re-evaluate the geographic groupings after the rapid expansion of the genus, we conducted phylogenetic analyses for begomovirus species representatives of the two longest and most conserved begomovirus proteins: the coat and replication-associated proteins. Both proteins still largely support the broad AAEO and Americas begomovirus groupings, except for sweet potato-infecting begomoviruses that form an independent, well-supported clade for their coat protein regardless of the region they were isolated from. Our analyses do not support more fine-scaled phylogeographic groupings. Monopartite and bipartite genome organizations are broadly interchanged throughout the phylogenies, and the absence of the V2/AV2 gene is highly reflective of the split between Americas and AAEO begomoviruses. We observe significant evidence of recombination within the Americas and within the AAEO region but rarely between the regions. We speculate that increased globalization of agricultural trade, the invasion of polyphagous whitefly vector biotypes and recombination will blur begomovirus phylogeographic delineations in the future.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142501929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michelle Gellhorn Serra, Lars Meier, Lucie Sauerhering, Jochen Wilhelm, Alexandra Kupke
{"title":"Organotypic brain slices as a model to study the neurotropism of the highly pathogenic Nipah and Ebola viruses.","authors":"Michelle Gellhorn Serra, Lars Meier, Lucie Sauerhering, Jochen Wilhelm, Alexandra Kupke","doi":"10.1099/jgv.0.002038","DOIUrl":"https://doi.org/10.1099/jgv.0.002038","url":null,"abstract":"<p><p>Nipah virus (NiV) and Ebola virus (EBOV) are highly pathogenic zoonotic viruses with case fatality rates of up to 90%. While the brain is a known target organ following NiV infection, involvement of the central nervous system in EBOV-infected patients only became more evident after the West African epidemic in 2013-2016. To gain a deeper comprehension of the neurotropism of NiV and EBOV with respect to target cells, affected brain regions and local inflammatory responses, murine organotypic brain slices (BS) were established and infected. Both NiV and EBOV demonstrated the capacity to infect BS from adult wt mice and mice lacking the receptor for type I IFNs (IFNAR<sup>-/-</sup>) and targeted various cell types. NiV was observed to replicate in BS derived from both mouse strains, yet no release of infectious particles was detected. In contrast, EBOV replication was limited in both BS models. The release of several pro-inflammatory cytokines and chemokines, including eotaxin, IFN-γ, IL-1α, IL-9, IL-17a and keratinocyte-derived chemokine (KC), was observed in both virus-infected models, suggesting a potential role of the inflammatory response in NiV- or EBOV-induced neuropathology. It is noteworthy that the choroid plexus was identified as a highly susceptible target for EBOV and NiV infection, suggesting that the blood-cerebrospinal fluid barrier may serve as a potential entry point for these viruses.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142501928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
John D Clarke, Helen M E Duyvesteyn, Eva Perez-Martin, Undīne Latišenko, Claudine Porta, Kathleen V Humphreys, Abigail L Hay, Jingshan Ren, Elizabeth E Fry, Erwin van den Born, Bryan Charleston, Marie Bonnet-Di Placido, Raymond J Owens, David I Stuart, John A Hammond
{"title":"A broadly reactive ultralong bovine antibody that can determine the integrity of foot-and-mouth disease virus capsids.","authors":"John D Clarke, Helen M E Duyvesteyn, Eva Perez-Martin, Undīne Latišenko, Claudine Porta, Kathleen V Humphreys, Abigail L Hay, Jingshan Ren, Elizabeth E Fry, Erwin van den Born, Bryan Charleston, Marie Bonnet-Di Placido, Raymond J Owens, David I Stuart, John A Hammond","doi":"10.1099/jgv.0.002032","DOIUrl":"https://doi.org/10.1099/jgv.0.002032","url":null,"abstract":"<p><p>Foot-and-mouth disease vaccination using inactivated virus is suboptimal, as the icosahedral viral capsids often disassemble into antigenically distinct pentameric units during long-term storage, or exposure to elevated temperature or lowered pH, and thus raise a response that is no longer protective. Furthermore, as foot-and-mouth disease virus (FMDV)'s seven serotypes are antigenically diverse, cross-protection from a single serotype vaccine is limited, and most existing mouse and bovine antibodies and camelid single-domain heavy chain-only antibodies are serotype-specific. For quality control purposes, there is a real need for pan-serotype antibodies that clearly distinguish between pentamer (12S) and protective intact FMDV capsid. To date, few cross-serotype bovine-derived antibodies have been reported in the literature. We identify a bovine antibody with an ultralong CDR-H3, Ab117, whose structural analysis reveals that it binds to a deep, hydrophobic pocket on the interior surface of the capsid via the CDR-H3. Main-chain and hydrophobic interactions provide broad serotype specificity. ELISA analysis confirms that Ab117 is a novel pan-serotype and conformational epitope-specific 12S reagent, suitable for assessing capsid integrity.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sian Lant, Alasdair J M Hood, Joe A Holley, Ailish Ellis, Lucy Eke, Rebecca P Sumner, David O Ulaeto, Carlos Maluquer de Motes
{"title":"Poxin-deficient poxviruses are sensed by cGAS prior to genome replication.","authors":"Sian Lant, Alasdair J M Hood, Joe A Holley, Ailish Ellis, Lucy Eke, Rebecca P Sumner, David O Ulaeto, Carlos Maluquer de Motes","doi":"10.1099/jgv.0.002036","DOIUrl":"10.1099/jgv.0.002036","url":null,"abstract":"<p><p>Poxviruses are dsDNA viruses infecting a wide range of cell types, where they need to contend with multiple host antiviral pathways, including DNA and RNA sensing. Accordingly, poxviruses encode a variety of immune antagonists, most of which are expressed early during infection from within virus cores before uncoating and genome release take place. Amongst these antagonists, the poxvirus immune nuclease (poxin) counteracts the cyclic 2'3'-GMP-AMP (2'3'-cGAMP) synthase (cGAS)/stimulator of interferon genes DNA sensing pathway by degrading the immunomodulatory cyclic dinucleotide 2'3'-cGAMP, the product of activated cGAS. Here, we use poxviruses engineered to lack poxin to investigate how virus infection triggers the activation of STING and its downstream transcription factor interferon-responsive factor 3 (IRF3). Our results demonstrate that poxin-deficient vaccinia virus (VACV) and ectromelia virus (ECTV) induce IRF3 activation in primary fibroblasts and differentiated macrophages, although to a lower extent in VACV compared to ECTV. In fibroblasts, IRF3 activation was detectable at 10 h post-infection (hpi) and was abolished by the DNA replication inhibitor cytosine arabinoside (AraC), indicating that the sensing was mediated by replicated genomes. In macrophages, IRF3 activation was detectable at 4 hpi, and this was not affected by AraC, suggesting that the sensing in this cell type was induced by genomes released from incoming virions. In agreement with this, macrophages expressing short hairpin RNA (shRNA) against the virus uncoating factor D5 showed reduced IRF3 activation upon infection. Collectively, our data show that the viral genome is sensed by cGAS prior to and during genome replication, but immune activation downstream of it is effectively suppressed by poxin. Our data also support the model where virus uncoating acts as an immune evasion strategy to simultaneously cloak the viral genome and allow the expression of early immune antagonists.</p>","PeriodicalId":15880,"journal":{"name":"Journal of General Virology","volume":"105 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}