Journal of Virology最新文献

{"title":"Extensive variation in virus-induced patterns of transposable element transcripts in <i>Drosophila</i>.","authors":"Camille A Mayeux, Chloé Garambois, Anaïs Larue, Julie Delescluse, Marie Fackeure, Vincent Lacroix, Hélène Henri, Natacha Kremer, Rita Rebollo, Séverine Chambeyron, Matthieu Boulesteix, Marie Fablet","doi":"10.1128/jvi.01071-26","DOIUrl":"https://doi.org/10.1128/jvi.01071-26","url":null,"abstract":"<p><p>Transposable elements (TEs) are widespread genomic parasites, whose activity is largely restrained by RNA interference pathways. Some of these pathways also contribute to antiviral immunity, allowing a mechanistic overlap that could generate interactions-or even trade-offs-between TE repression and viral defense. Here, we investigated this interplay by experimentally infecting two strains of <i>Drosophila melanogaster</i> and <i>Drosophila simulans</i> with three distinct viruses: <i>Drosophila</i> X virus (DXV), Flock House virus (FHV), and Invertebrate Iridescent virus 6 (IIV6). Through deep RNA-seq and small RNA-seq analyses, we show that viral infection consistently alters TE transcript abundance, although the direction and magnitude of these changes strongly depend on both the host strain and the virus. In addition, we provide an in-depth characterization of the dynamic TE repertoire that IIV6 carries.IMPORTANCETransposable elements (TEs) are genomic parasites that are found in all genomes. Here, using two strains of <i>Drosophila</i> and three viruses, we show that viral infections consistently affect TE transcript amounts. However, the magnitude and direction of the TE modulation depend on the host strain, the virus, and the tissue. In addition, one of the viruses under study, the Invertebrate Iridescent virus 6 (IIV6), carries TEs on its own, which we characterize as a dynamic repertoire.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0107126"},"PeriodicalIF":4.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137201","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":"Powassan virus LB neuroinvasion and lethality are determined by envelope protein domain III residues.","authors":"Marissa R Lindner, Elena E Gorbunova, Marcos Romario Matos de Souza, Grace E Himmler, Hwan Keun Kim, Erich R Mackow","doi":"10.1128/jvi.00963-26","DOIUrl":"10.1128/jvi.00963-26","url":null,"abstract":"<p><p>Powassan viruses (POWVs) are tick-borne orthoflaviviruses that cause lethal encephalitis and long-term neurologic sequelae. POWVs are divided into two lineages that share 86% genetic identity. POWV-LB (Lin I) was isolated from a fatal case of encephalitis, while POWV-LI9 (Lin II) is a tick-derived isolate that causes age-dependent lethality in mice. Domain III of orthoflavivirus envelope proteins (EDIII) directs cell attachment and determines murine neuropathology and lethality. Here, we developed POWV LB reverse genetics, analyzed brains of LB- and recLB mutant-infected mice, and assessed the role of EDIII residues in LB pathogenesis. LB infection of 50-week-old B6 mice focally activated microglia in the midbrain and cerebellum, discrete from and independent of the location of envelope protein in the cerebral cortex, hippocampus, and thalamus. Reverse genetic analysis of LB EDIII residues revealed that mutating D308N only partially reduced LB neuropathology and lethality. However, mutating D308N along with an adjacent EDIII residue, A310T, completely abolished LB-D308N/A310T neuroinvasion and lethality, yet elicited neutralizing antibody responses that protected mice from a lethal WT LB challenge. Signifying a change in neuroinvasion, LB-D308N/A310T failed to activate microglia or yield detectable POWV RNA and antigen in the CNS. Overall, recombinant LB-D308N/A310T mutants fail to induce neurologic symptoms or neuropathology while eliciting a protective immune response. These findings reveal that EDIII residues determine the neuroinvasion and lethality of lineage I POWVs and that genetically modifying EDIII provides a mechanism for POWV attenuation and vaccine development.IMPORTANCEPowassan virus causes lethal encephalitis and long-term neurological sequelae in survivors; however, there are currently no licensed POWV vaccines or therapeutics. POWVs are comprised of two genetic lineages (LB-Lin I and LI9 Lin II) that are derived from discrete ticks and small mammal hosts. Orthoflavivirus envelope proteins determine cell attachment, viral tropism, and neurovirulent spread and lethality in mice. Here, we created a POWV LB reverse genetics system and assessed mutations that determine LB neuroinvasion in 50-week-old mice. Studies reveal novel LB neuropathology with divergent patterns of gliosis and POWV antigen expression within the CNS. Mice subcutaneously infected with an LB-D308N/A310T envelope mutant elicited responses that protect mice from a lethal LB challenge and failed to enter the CNS or cause neurologic symptoms, CNS pathology, or lethality. LB reverse genetics permits defining the determinants of LB neuroinvasion that are required for rational vaccine development.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0096326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137286","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":"What a tangled web we weave: how agriculture, a polyphagous insect vector, and rampant recombination drove the emergence, evolution, and economic importance of the geminivirus beet curly top virus in western North America.","authors":"Tomas A Melgarejo, Li-Fang Chen, Mônica A Macedo, Margaret K Cespedes, Thomas Turini, William M Wintermantel, Robert L Gilbertson","doi":"10.1128/jvi.00840-26","DOIUrl":"https://doi.org/10.1128/jvi.00840-26","url":null,"abstract":"<p><p>Curly top disease (CTD) of sugar beet is characterized by leaf curling and stunted growth. Historic CTD emerged independently in western North America (~1900), South America (~1925), and the Middle East (~1955), following intensive cultivation of this Old World crop. In these regions, CTD is caused by genetically distinct monopartite geminiviruses transmitted by different leafhopper species. In North America, CTD is caused by 11 strains of beet curly top virus (BCTV) and transmitted by the beet leafhopper (BLH, <i>Circulifer tenellus</i>). Here, the emergence and evolution of BCTV and the role of agriculture were investigated using 133 genome sequences of isolates collected from multiple crops and locations over nearly a century, including 32 recent sequences from New World (NW) crops in California. New strains were not identified, and all isolates are recombinant and have four conserved breakpoints. Recombination-aware evolutionary analyses estimated BCTV emerged ~750 years ago, likely from a progenitor infecting uncultivated NW plants. Diversification was associated with the domestication of NW crops, especially pepper; the introduction of sugar beet; and the emergence of mild- and severe-type sugar beet strains. Overgrazing of grasses in foothills allowed proliferation of weed reservoirs of BCTV and BLH. Isolates recently collected from NW crops and weeds were mostly mild-type strains, revealing a strain shift. The C4 effector protein of mild-type strains is nearly completely disordered (99%) compared with 44% for severe-type strains, suggesting a role in adaptive evolution. Thus, the evolution of BCTV and CTD biology were driven by agricultural practices, genetic flexibility of BCTV, and the polyphagous BLH vector.IMPORTANCEThis study revealed how the emergence and evolution of beet curly top virus (BCTV) and curly top disease in the western United States beginning ~ 1900 was facilitated by agriculture. Results of historic and molecular genetic studies showed BCTV emerged and diversified during the domestication of New World (NW) crops and subsequently after the introduction and intensification of Old World sugar beet. Invasive dicot weeds colonizing overgrazed foothill areas provided reservoirs for BCTV and the beet leafhopper vector. The long evolutionary history of BCTV, mediated by recombination and genetic drift, resulted in strains adapted to sugar beet (severe-type) and NW crops (mild-type). Following reduced sugar beet cultivation in California, mild-type strains underwent population expansion and became predominant in NW crops, facilitated by a highly disordered C4 effector protein. Thus, the genetic flexibility of BCTV, the polyphagous vector, and changing agricultural practices drove the emergence and persistence of this economically important plant disease.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0084026"},"PeriodicalIF":4.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127654","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":"Humoral response against Epstein-Barr virus follows a strain-specific and HIV-driven pattern.","authors":"Eric D Eymard, Dicle Yalcin, Owen Ngalamika, Salum J Lidenge, John T West, Charles Wood","doi":"10.1128/jvi.01043-26","DOIUrl":"https://doi.org/10.1128/jvi.01043-26","url":null,"abstract":"<p><p>Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus causally linked to several malignancies, including lymphomas and solid tumors. Despite its high global prevalence, a comprehensive profile of humoral responses to EBV is yet to be described. Moreover, how HIV-1 co-infection influences this response can reveal new insights into how cancer risk increases in people with HIV-1 (PWH). Here, we employed phage immunoprecipitation and sequencing (PhIP-Seq) using the VirScan phage-display library to map antibody responses against the EBV proteome in 115 adults from sub-Saharan Africa, with and without HIV-1 co-infection (43 HIV-positive and 72 HIV-negative) at peptide-level resolution. We identified EBNA1, EBNA2, EBNA3B, and the viral capsid antigen protein BFRF3 as the most immunodominant EBV proteins. Differential antibody reactivities between EBV Type 1 and Type 2 were observed against EBNA2, with increased antibody recognition near the C-terminal transactivation domain (C-TAD) observed for Type 1. A specific region of EBNA1 containing the nuclear localization sequence (NLS) was the most frequently targeted epitope of the EBV proteome. Our comprehensive and high-resolution analysis identified several immunodominant EBV proteins that are targeted by most individuals regardless of HIV-1 status. HIV-1 co-infected individuals (PWH) had increased antibody recognition against most EBV proteins compared to HIV-uninfected individuals, but the magnitudes of those responses varied across the proteome. Overall, our findings suggest that HIV-1 co-infection alters both the breadth and magnitude of anti-EBV responses, potentially reflecting increased viral reactivation and HIV-driven mechanisms of immunosuppression that may impact the magnitude of antibody responses in EBV.IMPORTANCEThis study employs the first comprehensive high-resolution antibody profiling against Epstein-Barr virus (EBV) among healthy adults and people with HIV-1 (PWH). Our results indicated that HIV-1 has a considerable influence on the anti-EBV repertoire that may provide further evidence of how HIV-1 significantly increases the risk of EBV-associated malignancies such as lymphoma. We showed evidence that HIV-1 co-infection leads to higher exposure to viral antigens, likely due to viral reactivation, reflected by a higher percentage of patients with antibodies reactive to the majority of EBV proteins when compared to people without HIV-1. Since PWH are known to be more susceptible to EBV-associated cancers, whether these changes in humoral immune response can be used as prognostic biomarkers for cancer risks should be further investigated with longitudinal studies.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0104326"},"PeriodicalIF":4.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127417","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":"Pre-existing cross-subtype serological responses against H5Nx in health care workers.","authors":"Katrina Dionne, Étienne Bélanger, Mehdi Benlarbi, Guillaume Beaudoin-Bussières, Claudia Santos Saenz, Shilei Ding, Catherine Bourassa, Halima Medjahed, Morgan Jennings, Geneviève Laroche, Julie Carbonneau, Elie Haddad, Madeleine Durand, Guy Boivin, Marceline Côté, Andrés Finzi","doi":"10.1128/jvi.01310-26","DOIUrl":"https://doi.org/10.1128/jvi.01310-26","url":null,"abstract":"<p><p>A rise in cases of highly pathogenic avian influenza A (H5N1) clade 2.3.4.4b in humans has been reported since 2023. Although influenza seasonal vaccination (H1N1/H3N2) was shown to be effective against cases of reinfection with endemic influenza A viruses (IAVs), its capacity to elicit cross-reactive antibodies against (H5N1) remains unclear. Here, we measured vaccine-elicited antibody responses against seasonal (H1N1/H3N2) and various avian subtypes A (H5Nx) using plasma samples from the CRCHUM Health Care Workers cohort in Montreal, Canada, during the 2024 influenza seasonal vaccination. The capacity of their plasma to recognize hemagglutinin (HA) and neuraminidase (NA) antigens from ten influenza strains was measured. Their neutralizing activity, as well as their capacity to mediate antibody-dependent cellular cytotoxicity (ADCC) against cells stably expressing HA and NA, was measured. Overall, seasonal vaccination against H1N1/H3N2 elicited antibodies able to recognize several HA and NA, and in some individuals, this translated to increased neutralization and ADCC activity, including against H5Nx. This study provides insightful information on how vaccination shapes cross-reactive antibody responses against avian H5Nx.</p><p><strong>Importance: </strong>Influenza A viruses (IAVs) are endemic in the human population and responsible for hundreds of thousands of deaths every year, occasionally leading to influenza pandemics. Since 2023, there has been a rise in avian IAV infections in humans, with some deaths reported, mostly related to the H5N1 subtype clade 2.3.4.4b. Seasonal vaccines against IAVs are effective, but their efficacy against avian IAVs is not well known. Here, following influenza seasonal vaccination in a cohort of adults, we report highly heterogeneous serological responses, possibly due to pre-existing immunity and HA sequence similarity. These findings provide insight into the breadth of pre-existing and vaccine-induced immunity against H5 influenza viruses and may inform the development of vaccination strategies aimed at providing broader protection against emerging influenza viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0131026"},"PeriodicalIF":4.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127643","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":"Repurposing tretinoin, a vitamin A derivative, against Chikungunya virus infection.","authors":"Soumyajit Ghosh, Chandan Mahish, Archana Mahapatra, Tathagata Mukherjee, Pratima Kumari, Bijita Bhowmick, Saikat De, Udvas Ghorai, Rajshree Rajmohan Jena, Seema Pradhan, Subhasis Chattopadhyay, Soma Chattopadhyay","doi":"10.1128/jvi.00558-26","DOIUrl":"https://doi.org/10.1128/jvi.00558-26","url":null,"abstract":"<p><p>Chikungunya virus (CHIKV) has reemerged as a global pathogen causing serious public health threat, particularly due to the absence of specific antivirals. Retinoids, vitamin A derivatives, have demonstrated antiviral potential against different viral infections, yet their efficacy against alphaviruses has never been investigated. In this study, tretinoin (TR), or all-trans retinoic acid (ATRA), was evaluated for its anti-CHIKV activity using <i>in vitro</i>, <i>in vivo</i>, and <i>ex vivo</i> models. TR abrogated CHIKV infection efficiently in Vero and C2C12 cells, with a marked reduction (>90%) in viral RNA, proteins, and progeny formation. The IC₅₀ of TR against CHIKV was estimated to be 20.05 µM and 19.71 µM in Vero and C2C12 cells, respectively. Additionally, TR showed remarkable virucidal activity and effective inhibition during entry, as well as in the early stages of post-CHIKV infection. Next, the global transcriptome profile demonstrated that the \"signaling by retinoic acid\" pathway was significantly enriched after CHIKV infection, and retinoic acid receptors (RARs), specifically RAR-β, are the key mediators for the anti-CHIKV effect of TR. Further, the drug alters phosphorylated mitogen-activated protein kinases (MAPKs), NF-κB, and proinflammatory cytokines during CHIKV infection in RAW 264.7 cells. Interestingly, TR protected C57BL/6 mice from CHIKV challenge by diminishing viral burden, leading to reduced clinical scores and better survival. Similar observations were also noticed in the <i>ex vivo</i> models of CHIKV-infected primary human skeletal muscle myoblasts (HSMMs). In conclusion, this work demonstrated the repurposing potential of TR against CHIKV infection for the first time, encouraging its clinical validation toward future therapeutics.</p><p><strong>Importance: </strong>Chikungunya virus (CHIKV) is an arbovirus causing Chikungunya fever (CHIKF), leading to debilitating arthralgia and myalgia. The unavailability of licensed antivirals against CHIKV encourages extensive research to find a therapeutic cure. Retinoids, the derivatives of vitamin A, have been repurposed as antiviral agents against a broad range of viruses; however, their potency against alphaviruses remains unexplored. Accordingly, tretinoin (TR), also known as all-trans retinoic acid (ATRA), was validated for anti-CHIKV efficacy in this investigation. Significant perturbations of CHIKV titer, RNA, and protein levels were observed in the presence of TR following infection, and its antiviral effect was mediated through RAR-β. Moreover, the anti-CHIKV potential of TR was evaluated in the mouse model and primary human skeletal muscle myoblasts, indicating strong preclinical efficacy. Finally, this is the first study to report the antiviral property of TR against CHIKV infection using <i>in vitro</i>, <i>in vivo</i>, and <i>ex vivo</i> approaches, suggesting its repurposing potential.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0055826"},"PeriodicalIF":4.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127728","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":"Infection and transmission dynamics of bovine and human influenza A H5N1 viruses in mouse and hamster models.","authors":"Mohammed Nooruzzaman, David W Buchholz, Ruchi Rani, Pablo Sebastian Britto de Oliveira, Richard A Adeleke, Chen Feng, Nicholas Vazquez, Elena A Demeter, Hector C Aguilar, Diego G Diel","doi":"10.1128/jvi.01044-26","DOIUrl":"https://doi.org/10.1128/jvi.01044-26","url":null,"abstract":"<p><p>Here we investigated the pathogenesis and contact transmission of bovine- and human-derived highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b genotype B3.13 viruses in mammalian models. Using reverse genetics, we rescued three naturally occurring viruses, rTX2/24 (bovine-derived), rTexas/37, and rMichigan/90 (both human-derived), and compared their infection dynamics, replication, and pathogenicity with the wild-type bovine TX2/24 strain <i>in vitro</i> and <i>in vivo</i>. All four viruses demonstrated comparable replication kinetics in four mammalian cell lines. However, the rMichigan/90 strain exhibited smaller plaques in bovine and human cells. <i>In vivo</i> studies showed that mice infected with any of the viruses succumbed to infection within 4-5 days; however, mice infected with the rMichigan/90 virus exhibited slightly lower viral replication and shedding compared with the other strains. The hamster model showed a milder infection phenotype than mice in which all viruses induced body weight loss and oral shedding, with robust virus replication observed in tissues, but the rMichigan/90 virus presented reduced replication and shedding. Contact transmission studies in hamsters revealed limited transmissibility for these viruses, with only one out of four animals inoculated with the rMichigan/90 virus transmitting it to a naïve contact. These findings indicate that both bovine- and human-derived H5N1 genotype B3.13 viruses present high pathogenicity in rodent models, though the overall respiratory transmissibility remains low in the hamster model.IMPORTANCEInfluenza A H5N1 virus spilled over from wild birds into dairy cattle in the United States in 2024. Since then, an increased number of human infections-with at least 71 confirmed cases-have been confirmed. In the present study, we evaluated and compared the pathogenicity and transmissibility of a bovine and two human H5N1 viruses of the genotype B3.13. Our results show that while all viruses are pathogenic in mouse and hamster models, the bovine isolate TX2/24 presents a broader tissue tropism than the human-derived viruses. Contact transmission studies revealed a limited ability of these viruses to transmit in the hamster contact transmission model. These findings highlight the high pathogenicity of H5N1 viruses in mammals and demonstrate that their respiratory transmissibility potential remains low in the hamster model.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0104426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111491","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":"Endogenous anti-Ebola virus GP_1,2 antibodies interfere with detection of secreted glycoprotein in the blood of EVD patients.","authors":"Patrick T Tshita, Aurélie Ploquin, John Misasi, Bobo N Bazola, Samuel M Shamamba, Hadar Marcus, Ange Y Mubiala, Francis M Ntumba, Saidou Milua, Courtney Tucker, Eddy Kinganda-Lusamaki, Emmanuel Lokilo, Raphael Lumbembe, Aziza Amuri, Naomie Bayoka, Anthony Suangi, Christian M Kahusu, Ilombe Myriam Mbilizi, Olivier Tshiani-Mbaya, Denis K Kandolo, Placide Mbala-Kingebeni, Sabue Mulangu, Jean-Jacques Muyembe-Tamfum, Nancy J Sullivan, Dacquin M Kasumba","doi":"10.1128/jvi.01414-26","DOIUrl":"https://doi.org/10.1128/jvi.01414-26","url":null,"abstract":"<p><p>Ebola disease (EBOD) is a highly infectious disease with severe hemorrhagic symptoms. It is caused by orthoebolaviruses<i>,</i> which include the Ebola virus (<i>Orthoebolavirus zairense</i>) (EBOV) causing Ebola virus disease (EVD), the most lethal EBOD to humans. Through co-transcriptional polymerase stuttering and subsequent proteolytic processing, its <i>GP</i> gene produces multiple protein products, including secreted glycoprotein (sGP) and structural membrane-associated trimeric GP_1,2. Although sGP is known to circulate in the blood, its physiological significance in disease pathology remains speculative. We quantified sGP using enzyme-linked immunosorbent assay (ELISA) in 36 acute human EVD cases from the 10th and 11th EVD outbreaks in the Democratic Republic of the Congo (DRC) using single-time-point biobanked samples. We detected and quantified sGP in four patients with strong <i>GP</i> gene transcription (GP Ct < 25), as evidence of viral replication, but with no endogenous anti-EBOV GP_1,2 IgG. However, sGP was not quantified in patients with lower GP transcription (Ct > 25), regardless of their anti-EBOV GP_1,2 IgG results. While two patients, MAM179 and MAM271, had notably strong GP transcription (Ct < 25), their high amounts of endogenous anti-EBOV GP_1,2 IgG might have interfered with detection by the assay detection antibody, a human anti-EBOV GP_1,2/sGP IgG. Furthermore, the addition of sera containing anti-EBOV GP_1,2 IgG reduced the binding between sGP and anti-EBOV GP_1,2/sGP used as detection antibodies. This suggested that the level of sGP in circulation is strongly linked to the intensity of <i>GP</i> transcription. Additionally, circulating sGP in this context would form complexes with anti-GP_1,2 antibodies, hence hindering additional antibody binding for detection.IMPORTANCEInsight into the mechanism of immune function by the Ebola virus secreted glycoprotein (sGP) in humans is essential for better understanding viral pathogenesis, immune protection, and immune evasion strategies. Research utilizing samples from patients who are infected with or have survived infection with the Ebola virus offers an unparalleled opportunity to determine the immunological significance of sGP. This research evaluates, in acutely infected patients from Ebola virus disease outbreaks, the role of EBOV sGP in modulating antibody responses directed against viral entry glycoprotein. By elucidating how sGP influences antibody-mediated immunity, the study advances our understanding of a conserved immune-evasion mechanism shared across all orthoebolaviruses. These investigations are valuable resources for designing more efficacious vaccines, therapies, and biomarkers for monitoring Ebola virus diseases.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0141426"},"PeriodicalIF":4.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111444","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":"<i>In vitro</i> and <i>in vivo</i> model systems for <i>Orthoflavivirus</i> antiviral therapeutics: current landscape and strategic considerations.","authors":"Marnix Van Loock, Tobias Nilsson, James F Demarest, Timothy Tellinghuisen, Ruxandra Draghia-Akli","doi":"10.1128/jvi.01011-26","DOIUrl":"https://doi.org/10.1128/jvi.01011-26","url":null,"abstract":"<p><p>Orthoflaviviruses represent an escalating global health challenge, encompassing a diverse group of arthropod-borne viruses that cause substantial morbidity and mortality worldwide. A critical bottleneck in drug discovery is identifying <i>in vitro</i> and <i>in vivo</i> models that accurately recapitulate human pathophysiology while remaining practical for high-throughput screening and medicinal chemistry efforts. Despite substantial preclinical activity, the paucity of clinically advanced <i>Orthoflavivirus</i> (hereafter referred to as flaviviruses) antivirals underscores the need for improved discovery paradigms. Refinement of antiviral assays, informed by viral biology and guided by rigorous validation principles, will be central to identifying robust small-molecule inhibitors. The convergence of high-quality phenotypic assays, precise target-based methods, and physiologically relevant models offers a promising path forward for flavivirus drug discovery and development.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0101126"},"PeriodicalIF":4.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111305","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":"TLR3-TRIF signaling in villus-like enterocytes drives type III interferon responses to enteroviruses.","authors":"David N Hare, Carolyn B Coyne","doi":"10.1128/jvi.01348-26","DOIUrl":"https://doi.org/10.1128/jvi.01348-26","url":null,"abstract":"<p><p>Enteroviruses initiate infection at the intestinal epithelium but can spread systemically to cause severe disease. Although both MDA5 and TLR3 have been implicated in enterovirus sensing, the mechanisms by which the intestinal epithelium detects these viruses remain poorly defined. To address this, we infected human intestinal organoids (enteroids) with the group B enterovirus echovirus 11 (E11) and compared responses in models differentiated to mimic either crypt-like or villus-like epithelium. Villus-like enteroids produced significantly more type III interferons following E11 infection and exhibited heightened responsiveness to type III interferon signaling. Single-cell RNA sequencing of infected enteroids revealed that E11 broadly infected epithelial cell types, but type III interferon expression was largely restricted to mature enterocytes. Notably, enterocyte differentiation was also associated with upregulation of TLR3 and other innate immune genes. Using CRISPR-Cas9 knockout enteroids, we found that TLR3-TRIF signaling was essential for intestinal type III IFN responses to E11 infection, whereas loss of MAVS, the adaptor for MDA5, had no effect. Together, these data support a model in which mature enterocytes serve as key sensors of enterovirus infection via TLR3-TRIF signaling, triggering a localized type III IFN response that may help restrict viral spread.</p><p><strong>Importance: </strong>Enteroviruses are commonly circulating viruses that can cause a broad spectrum of disease, particularly in pediatric populations. Innate immune sensing in the intestinal epithelium likely plays a critical role in determining the outcome of enterovirus infections. Deficiencies in TLR3 signaling, type III IFN responses, or crypt-villus architecture may contribute to severe disease presentations. Our findings highlight the importance of TLR3-mediated sensing in mature enterocytes, which may also have broader implications for other intestinal viruses, as well as for inflammatory conditions like inflammatory bowel disease. A deeper understanding of how TLR3 sensing and type III IFN production are regulated in the intestine could inform new therapeutic strategies aimed at modulating mucosal sensitivity to viral nucleic acids and enhancing antiviral defense.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":" ","pages":"e0134826"},"PeriodicalIF":4.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111576","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}