搜索结果：Virologica Sinica

Tick-borne viruses (TBVs) pose significant emerging threats to public and veterinary health worldwide. In Pakistan, the potential threats posed by TBVs extend far beyond Crimean-Congo hemorrhagic fever virus (CCHFV), which causes outbreaks and severe hemorrhaging with a high fatality rate among humans each year. However, the full extent of the tick-borne virome remains largely unexplored. This study presents the metagenomic profiling of viruses in livestock-associated ticks from Pakistan. Eighty-seven ticks belonging to the genera Ixodes, Rhipicephalus, Haemaphysalis, and Hyalomma species from livestock in Punjab. These ticks were subsequently grouped into 11 pools for RNA sequencing. Our analysis revealed extensive viral diversity, identifying sequences related to 31 viruses spanning at least 11 families. New strains of Jingmen tick virus (JMTV), Brown dog tick phlebovirus 2 (BDTPV-2), and Liman tick virus (LMTV) were characterized, confirming their presence in the region. Serological surveys performed among 319 livestock, 253 humans, and 214 rats detected antibodies against these viruses, indicating host exposure. Notably, the presence of JMTV-neutralizing antibodies was confirmed in two livestock animals, one human, and one rat, providing evidence of productive infection. Our findings significantly expand the known diversity and distribution of TBVs in Pakistan, establish the preliminary baseline of the tick virome in the country, and provide serological evidence of cross-species exposure to emerging TBVs. This study highlights the underestimated risk of tick-borne viral zoonoses in Pakistan and underscores the urgent need for enhanced surveillance and risk assessment.

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H9N2 avian influenza viruses (AIVs), which are enzootic in poultry and possess spillover potential to humans, represent a considerable global public health threat. Since 2021, we have observed an unprecedented decline in the ability of H9N2 viruses to agglutinate chicken red blood cells (CRBCs), a change that impairs effective detection in routine surveillance. Substituting CRBCs with turkey or guinea pig erythrocytes in hemagglutination assays effectively restored virus detectability. Through integrated bioinformatic and biological approaches, we identified that this phenotype is associated with specific amino acid substitutions at residues 131 and 132 of the 130-loop in the hemagglutinin (HA) protein. The HA motif 131/132-NT emerged in 2015 and rapidly increased in frequency, becoming the dominant pattern since 2021 in chickens and humans. Critically, the 131/132-NT motif attenuated viral binding affinity to short-chain α2,6-linked sialic acid receptors, explaining the loss of agglutination with CRBCs. Animal experiments further demonstrated that viruses carrying the HA 131/132-NT mutations maintained strong infectivity in chickens but altered tissue tropism in mice, showing reduced replication in the lungs. Collectively, our findings reveal a potential surveillance gap caused by reduced hemagglutination activity of H9N2 viruses, which may compromise the sensitivity of CRBC-based detection and potentially lead to under-detection of circulating viruses. Incorporating turkey or guinea pig red blood cells into surveillance protocols is therefore recommended to enhance detection sensitivity.

Foot-and-mouth disease virus (FMDV), a highly contagious picornavirus, employs multifaceted strategies to evade host innate immunity, with viral proteins 3C protease (3Cpro) and 2B serving as key immune antagonists. The stimulator of interferon genes 1 (STING1) is a critical innate immune adaptor; however, its role and regulatory mechanisms during FMDV infection remain incompletely understood. Here, we report that STING1 inhibits FMDV replication through an interferon (IFN)-independent mechanism, while FMDV counteracts this antiviral effect by degrading STING1 via 3Cpro and 2B. Mechanistically, FMDV 3Cpro mediates STING1 degradation in a protease activity-dependent manner; this STING1-degrading activity is conserved among 3Cpro proteins of poliovirus, enterovirus 71, and coxsackievirus, but not senecavirus A. In contrast, FMDV 2B suppresses STING1 expression at the mRNA level, and neither proteasomal, lysosomal, nor caspase pathways are involved in 3Cpro/2B-mediated STING1 downregulation. Furthermore, the STING1 stabilizer SB24011 enhances endogenous STING1 expression, dose-dependently inhibits FMDV replication by targeting viral internal ribosome entry site (IRES)-mediated translation, and exhibits broad-spectrum antiviral activity against multiple picornaviruses. In vivo, SB24011 treatment alleviates virus-induced histopathological lesions. Collectively, our findings reveal a novel IFN-independent antiviral role of STING1 against FMDV, identify 3Cpro and 2B as FMDV-encoded STING1 antagonists, and highlight the potential of SB24011 as a broad-spectrum anti-picornavirus therapeutic agent.

Human adenoviruses (HAdVs), particularly subgroup B serotypes HAdV-3 and HAdV-55, are associated with severe respiratory disease and currently lack targeted therapies. While neutralizing monoclonal antibodies (nMAbs) offer promising therapeutic potential, the specific nMAbs targeting these serotypes remain poorly characterized. Therefore, this study aimed to generate and evaluate the efficacy of serotype-specific nMAbs against HAdV-3 and HAdV-55. Mice were immunized with HAdV-3 virions, HAdV-55 virions, or recombinant fiber knob proteins (HAdV-55/-7) for the generation of serotype-specific nMAbs, and their efficacy was systematically evaluated using in vitro assays and an in vivo tree shrew model. Through comprehensive screening, eleven MAbs were identified with specificity against HAdV-3 (six clones) or HAdV-55/-7 fiber knob (five clones). Four nMAbs exhibited potent neutralizing activity: 13F12 (half-maximal inhibitory concentration, IC50: 3.8 &#x3bc;g/mL), 8D2 (IC50: 15.1 &#x3bc;g/mL), 3A3 (IC50: 14.9 &#x3bc;g/mL) against HAdV-3 virions, and 8F2 with neutralizing efficacy against HAdV-55 virions (IC50: 30.4 &#x3bc;g/mL). Western blot analysis revealed that MAbs 13F12 and 8F2 targeted the fiber protein, whereas 8D2 and 3A3 bound to the hexon protein. Furthermore, in vivo evaluations demonstrated that 13F12 significantly reduced viral loads in nasal turbinates and attenuated lung pathology in HAdV-3-infected tree shrews. Mechanistically, all tested anti-HAdV-3 nMAbs inhibited infection by blocking viral attachment (P < 0.01 vs. controls). In conclusion, this study underscores the therapeutic potential of targeting viral entry and highlights 13F12 as a promising candidate for HAdV prophylaxis.

&#x2022; A novel BAC of HSV-1 F-strain was generated by synthetic biology. &#x2022; The BAC sequence could be removed from F-BAC via in vitro Cre-LoxP recombination. &#x2022; The resulting F-BAC&#x394; virus shows replication property similar to the wild-type virus.

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Mollusca, the second-largest animal phylum, includes many aquaculture species used as important food resources for humans. While DNA viruses that threaten molluscan aquaculture have received much attention, molluscan RNA viromes are still understudied. Here, using a multi-stage RdRP discovery pipeline combining six-frame translation, profile-based homology search, and phylogenetic validation, 203 RNA viruses spanning five viral phyla and fifteen viral orders were identified, based on 223 molluscan metatranscriptomes covering eight classes. Phylogenetic analysis, combined with structural modeling, revealed a significant increase in the number of Pisuviricota-related lineages. Extensive modular evolution in viral genomes was observed, including gene rearrangements and co-evolution of capsid and RdRP genes. Host prediction linked 76% of the RNA viruses to a range of eukaryotes. These findings expand the diversity of RNA viruses associated with molluscs and shed light on their phylogenetic relationships, highlighting that molluscs might serve as an important reservoir of diverse RNA viruses infecting a range of eukaryotic hosts.

The evolution of SARS-CoV-2 has been driven by successive globally circulating waves, including the Alpha and Delta lineages, early Omicron (BA.1-BA.5), XBB, and the recently dominant JN.1 lineages. Although the marked advantage in fitness of early Omicron over Delta lineages has been recognized, there is a lack of systematic evaluation of SARS-CoV-2 fitness across 2020 to 2025. Here, we analyzed 15.23 million SARS-CoV-2 genomes available through May 2025. The accumulation of mutations in the spike protein of the virus has continued to accelerate over time, whereas the trend slowed in the other viral proteins. Using a Bayesian genomic-epidemiological framework, we estimated that lineage fitness increased approximately linearly from 2021 to 2025. Notably, JN.1 lineages exhibited a significantly higher rate of fitness gain than their predecessor XBB and earlier Omicron lineages. We further analyzed characteristic mutations of JN.1 and found that those in the receptor-binding domain were associated with larger alterations in residue hydropathy, charge, and structural surface exposure relative to other lineages. These findings suggest JN.1 as a distinct evolutionary stage and underscore the importance of sustained genomic surveillance.

Enterovirus A71 (EV-A71) is the primary pathogen causing severe hand-foot-and-mouth disease (HFMD) in young children, with T-cell immune dysfunction closely linked to severe clinical outcomes. However, the molecular mechanisms underlying EV-A71-mediated T-cell impairment remain unclear, and no specific therapies are currently available. Here, we investigated the interaction between EV-A71 and T cells, and explored potential targeted therapeutic strategies. Our results showed that EV-A71 efficiently infects T cell lines (Jurkat, EL-4) and primary mouse CD3+ T cells in a dose- and time-dependent manner, inducing T-cell death and upregulating pro-inflammatory cytokines (IL-1&#x3b2;, IL-6, TNF-&#x3b1;). Mechanistically, EV-A71 infection triggers GSDME-dependent pyroptosis in T cells via caspase-3 activation, rather than GSDMD-dependent pyroptosis, as evidenced by genetic ablation and inhibitor experiments. Methylcobalamin (MeCbl), a specific GSDME inhibitor, rescued EV-A71-induced T-cell loss, and significantly improved the survival rate (80%) of EV-A71-infected newborn mice. Furthermore, the combined treatment with MeCbl and AGS-A (a T cell-dependent therapeutic agent) exerted a synergistic protective effect, achieving 90% survival rate in wild-type mice, which was abrogated in T cell-deficient BALB/c-nu-/- mice. Collectively, our findings identify GSDME-dependent T-cell pyroptosis as a key pathogenic mechanism of EV-A71 infection and highlight MeCbl as a promising targeted agent for HFMD treatment, either used alone or in combination with AGS-A.

Human immunodeficiency virus type 1 (HIV-1) Tat is essential for efficient viral transcription and replication, and its stability is tightly controlled by host factors. In our previous study, we showed that ZNF598 stabilizes Tat and promotes HIV-1 replication through an E3 ligase activity-independent mechanism. Here, we identify FAT10 as a critical mediator of this effect. FAT10 knockout in HEK293T cells or FAT10 knockdown in Jurkat T-cell infection models markedly impaired the ability of ZNF598 to suppress Tat K48-linked ubiquitination, increase Tat abundance, and enhance HIV-1 replication. Mechanistically, FAT10 reduced Tat K48-linked ubiquitination, stabilized Tat, and promoted HIV-1 transcription and replication. Direct GST pull-down assays further demonstrated that FAT10 directly binds Tat in vitro, and this interaction was retained by a FAT10 mutant lacking the C-terminal diglycine motif, supporting a predominantly non-covalent mechanism rather than canonical FAT10ylation. Consistently, ZNF598 enhanced the FAT10-Tat interaction, whereas ZNF598 knockdown attenuated FAT10-mediated Tat stabilization and proviral effects. In addition, the N-terminal 1-32 amino acids of Tat were required for responsiveness to both ZNF598 and FAT10. Finally, FAT10 expression was increased in HIV-1-infected cells and in CD4+ T cells from HIV-infected individuals, where it was associated with clinical markers of disease activity and viral load. Together, these findings define a ZNF598-FAT10-Tat regulatory axis that promotes HIV-1 transcription and replication.

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes debilitating febrile and arthritic disease and remains a persistent public health threat in tropical and subtropical regions, with no clinically approved antiviral drugs currently available, which underscores the urgent need for targeted and effective therapeutic interventions. Through high-throughput screening of an FDA-approved compound library, we identified retinoic acid (RA) as a broad-spectrum inhibitor of multiple arboviruses, exhibiting potent activity against CHIKV. Time-of-addition experiments, together with assays on viral binding, endocytosis, membrane fusion, replication and translation, were performed to determine the specific lifecycle stages inhibited by RA. Notably, RA exerts anti-CHIKV effects by selectively targeting eukaryotic translation initiation factor 4B (EIF4B), thereby disrupting the viral translation, as revealed by limited proteolysis-mass spectrometry (LiP-MS). And, our results demonstrated that RA administration exerted potent protective effects against CHIKV infection in vivo. Specifically, RA significantly reduced cerebral pathological damage, relieved clinical manifestations, and enhanced survival in a murine model of CHIKV-induced encephalitis, while also markedly attenuating footpad swelling and joint pathological alterations in a CHIKV-induced arthritis mouse model. Collectively, our findings highlight RA as a promising anti-CHIKV candidate targeting EIF4B, supporting its further development as a therapeutic agent against CHIKV infection.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes a life-threatening infectious disease with high mortality. Currently, there are no approved vaccines or specific therapeutic drugs for clinical use against SFTSV infection. Here, we screened a lignan compound library to identify candidates with anti-SFTSV activity. Two type I arylnaphthalide lignan lactones, Pronaphthalide A and Procumbenoside I, were identified as potent inhibitors of SFTSV infection. Mechanistic investigations indicated that these lignans exert their inhibitory effects at the viral binding and internalization stages. Molecular docking analysis revealed that these lignans can bind to the conserved B domain of the SFTSV glycoprotein Gn, an interaction validated by subsequent experiments as the core mechanism underlying their antiviral activity. In a mouse model of lethal SFTSV infection, treatment with these compounds, particularly Procumbenoside I, significantly inhibited viral infection, attenuated histopathological abnormalities, and improved survival rates. The antiviral activity of these lignans was further expanded to other bunyaviruses, including Lymphocytic choriomeningitis virus (LCMV) and Wetland virus (WELV). These findings uncover the broad-spectrum antiviral activity of type I arylnaphthalide lignans and support their potential as candidate therapeutic agents for the clinical intervention of bunyavirus infections.

Enterovirus (EV) infections represent a significant global and national health concern in children, leading to various complications. Although most children with EV infections generally have a favorable prognosis, a small proportion may still develop severe complications. This study aimed to analyze the epidemiological characteristics, disease spectrum, and disease burden of EV infections in China. A total of 163,714 hospitalized children with EV infections from 37 member hospitals of the Futang Research Center of Pediatric Development were identified between Jan 1st, 2016 and Dec 31st, 2023, accounting for 1.49% of all pediatric hospitalizations. Most cases occurred in infants aged 28 days to &#x2264; 1 year (42.29%) and toddlers aged 1 to &#x2264; 3 years (39.93%), with a male predominance (male-to-female ratio, 1.62 : 1). Severe cases of EV infections can be life-threatening and increase the burden of disease. The median LOS for EV infections were 5 days, with an average hospitalization cost of $587.37. EV infections can affect multiple organs, including the heart, brain, and respiratory system and were associated with severe complications, including myocarditis, encephalitis, and meningitis. These findings underscore the substantial disease burden of EV infections and highlight the need for targeted prevention strategies in young children.

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African swine fever (ASF), caused by the African swine fever virus (ASFV), is characterized by high mortality in infected pigs. ASFV infection triggers severe inflammatory response in the host, which is a crucial contributor to the high lethality of this disease. However, the underlying mechanism by which ASFV infection induces inflammatory response is still poorly understood. In this study, we found that UV-inactivated ASFV induces interleukin-1&#x3b2; (IL-1&#x3b2;) production, suggesting that certain structural proteins incorporated in the virion possess the ability to trigger inflammatory response. Further investigations demonstrated that deletion of the ASFV A137R gene significantly inhibited the ASFV-induced upregulation of the mRNA transcription of various proinflammatory genes and phosphorylation of p65 and I&#x3ba;B&#x3b1;. Furthermore, the purified pA137R protein promoted the mRNA transcription of these proinflammatory genes and phosphorylation of p65 and I&#x3ba;B&#x3b1;. Additionally, pA137R protein interacted with the NACHT and LRR domains of NLRP3 through its N terminal 1-99 amino acid domain, thereby promoting the oligomerization of NLRP3 and ASC and subsequently facilitating NLRP3 inflammasome assembly. Collectively, our findings identify ASFV pA137R protein as a key proinflammatory determinant of ASFV, which not only advances our understanding of the molecular mechanisms underlying ASFV-induced inflammatory response but also provides new insights into ASFV pathogenesis.

Herpes simplex virus type 1 (HSV-1) infection can induce herpes simplex encephalitis (HSE), a life-threatening neurological disorder characterized by active viral replication within the central nervous system accompanied by excessive neuroinflammatory responses. Cepharanthine hydrochloride (CH) is a natural bisbenzylisoquinoline alkaloid with diverse pharmacological activities. CH was evaluated for its antiviral and anti-inflammatory activities against HSV-1 infection. In microglia, CH markedly inhibited viral replication and suppressed STING-NF-&#x3ba;B signaling, thereby reducing HSV-1-associated neuroinflammation. During HSV-1 infection, CH binds to Nrf2, disrupting Keap1-Nrf2 interaction and subsequent ubiquitination. This hindered Nrf2 degradation and attenuated STING activation. In an HSE mouse model, CH significantly reduced viral loads in brain tissue, improved survival rates, prevented weight loss, and alleviated neurological symptoms. Furthermore, CH promoted the accumulation of Nrf2 and inhibited the STING-NF-&#x3ba;B signaling pathway in vivo. Collectively, these results indicate that CH represents a potential antiviral strategy for HSE.

The recent global outbreak of mpox virus (MPXV) infections underscores the urgent need for antiviral therapies against orthopoxviruses. In this study, using a high-content screening (HCS) platform based on a modified vaccinia virus Tiantan strain with GFP insertion (MVTT-GFP) under BSL-2 conditions, we screened 1513 kinase inhibitors for antiviral activity. Among these, Bruton's tyrosine kinase inhibitor BTKi-2 emerged as a potent candidate, exhibiting IC50 of 0.535 &#x3bc;M against vaccinia virus (VACV) and 0.260 &#x3bc;M against MPXV in vitro, while maintaining low cytotoxicity. In a murine model of VACV-induced pneumonia, BTKi-2 treatment reduced lung viral loads by 90% and a significantly improved survival compared to vehicle-treated controls. Notably, mechanistic studies indicate that BTKi-2's antiviral effects cannot be completely attributed to the inhibition of BTK or EGFR/ErbB2 signaling. These findings highlight BTKi-2 as a promising antiviral agent in vitro and in vivo, suggesting that BTKi-2 may offer a potential avenue for future therapeutic development against orthopoxvirus infections.

Host restriction factors and viral evasion strategies involved in the virus-host arms races remain to be discovered. Through an initial membrane protein-targeted CRISPR-Cas9 screening, we identified Acyl-CoA synthetase long-chain family member 3 (ACSL3) as a restriction factor against influenza A virus (IAV). Clinical transcriptomic analysis shows that ACSL3 is upregulated in peripheral blood mononuclear cells from mildly ill patients with influenza. Ectopic expression and loss-of-function validation demonstrate the physiological role of ACSL3 in restricting viral proliferation of diverse IAV subtypes (H1N1, H3N2, H3N8) in vitro and in vivo. Mechanistically, ACSL3 potentiates the antiviral unfolded protein response (UPR) by engaging the endoplasmic reticulum (ER) stress sensors IRE1&#x3b1; and PERK, thereby enhancing the IRE1&#x3b1;-XBP1-s driven inflammation and inhibiting the PERK-ATF4-CHOP mediated apoptosis. Conversely, IAV triggers the lysosomal degradation of ACSL3 and thus reprograms UPR to promote an immunologically silent apoptosis for viral egress and dissemination. Our findings establish ACSL3 as a molecular switch balancing the UPR-mediated antiviral response, and reveal a targeted viral evasion strategy in the virus-host interplay.