Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response...Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.展开更多
Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in ...Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells.Here,we demonstrate that the stimulator of interferon genes(STING)strengthens the host IFNindependent anti-hantaviral immunity.HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress,which further facilitates the subcellular translocation and activation of STING.During this process,STING triggers cellular autophagy by interacting with Rab7A,thus restricting viral replication.To note,the anti-hantaviral effects of STING are independent of canonical IFN signaling.Additionally,neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo.However,the administration of plasmids exogenously expressing the mutant C-terminal tail(ΔCTT)STING,which would not trigger the type I IFN responses,protected the nude mice from lethal HTNV infection.In summary,our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway,which offered novel therapeutic strategies against hantavirus infection.展开更多
Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Reveali...Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets. This study took advantage of the integration analysis of metabolomics and transcriptomics to depict the metabolic profiles of neurons during the early stage of JEV infection. Increased glycolysis and its branched pentose phosphate pathway(PPP) flux and impaired oxidative phosphorylation(OXPHOS) in glucose utilization,and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons. Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indispensable role in maintaining the optimal propagation of JEV. In addition, analysis of metabolomic-transcriptomic regulatory network showed the pivotal biological function of lipid metabolism during JEV infection. Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis.These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.展开更多
Crimean-Congo hemorrhagic fever virus(CCHFV)is regarded as one of the most deadly viruses,with mortality of up to 40%.Currently,no licensed vaccine with validated efficacy against CCHFV is available.CCHFV uses Gn and ...Crimean-Congo hemorrhagic fever virus(CCHFV)is regarded as one of the most deadly viruses,with mortality of up to 40%.Currently,no licensed vaccine with validated efficacy against CCHFV is available.CCHFV uses Gn and Gc glycoproteins to bind and penetrate the cell,like other bunyaviruses(Hulswit et al.,2021).Thus,the desired vaccines are needed,to elicit a potent neutralizing antibody(NAb)response to counteract this process.展开更多
Correction to:Virologica Sinica https://doi.org/10.1007/s12250-021-00445-0 In the original version of this article,one image in Fig.4 was accidently duplicated during figure layout and the dilution rate was mislabeled.
Due to the overlapping epidemiology and clinical manifestations of flaviviruses,differential diagnosis of these viral diseases is complicated,and the results are unreliable.There is perpetual demand for a simplified,s...Due to the overlapping epidemiology and clinical manifestations of flaviviruses,differential diagnosis of these viral diseases is complicated,and the results are unreliable.There is perpetual demand for a simplified,sensitive,rapid and inexpensive assay with less cross-reactivity.The ability to sort distinct virus particles from a mixture of biological samples is crucial for improving the sensitivity of diagnoses.Therefore,we developed a sorting system for the subsequent differential diagnosis of dengue and tick-borne encephalitis in the early stage.We employed aptamer-modified polystyrene(PS)microspheres with different diameters to specifically capture dengue virus(DENV)and tick-borne encephalitis virus(TBEV),and utilized a traveling surface acoustic wave(TSAW)device to accomplish microsphere sorting according to particle size.The captured viruses were then characterized by laser scanning confocal microscopy(LSCM),field emission scanning electron microscopy(FE-SEM)and reverse transcription-polymerase chain reaction(RT‒PCR).The characterization results indicated that the acoustic sorting process was effective and damage-free for subsequent analysis.Furthermore,the strategy can be utilized for sample pretreatment in the differential diagnosis of viral diseases.展开更多
基金This work was supported in whole or in part by the National Natural Science Foundation of China(82172272,31970148 and 82222367)the Key Research and Development Program of Shaanxi(2021ZDLSF01-05 and 2021ZDLSF01-02).
文摘Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.
基金supported by grants from the National Natural Science Foundation of China (No.31970148,82172272 and 82202367)the Key Research and Development Program of Shaanxi (2021ZDLSF01-02 and 2021ZDLSF01-05).
文摘Hantaan virus(HTNV),the prototype virus of hantavirus,could escape innate immunity by restraining type I interferon(IFN)responses.It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells.Here,we demonstrate that the stimulator of interferon genes(STING)strengthens the host IFNindependent anti-hantaviral immunity.HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress,which further facilitates the subcellular translocation and activation of STING.During this process,STING triggers cellular autophagy by interacting with Rab7A,thus restricting viral replication.To note,the anti-hantaviral effects of STING are independent of canonical IFN signaling.Additionally,neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo.However,the administration of plasmids exogenously expressing the mutant C-terminal tail(ΔCTT)STING,which would not trigger the type I IFN responses,protected the nude mice from lethal HTNV infection.In summary,our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway,which offered novel therapeutic strategies against hantavirus infection.
基金This research was funded by the National Major Science and Technology Projects of China,grant number 2017ZX10202203-007-003.
文摘Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets. This study took advantage of the integration analysis of metabolomics and transcriptomics to depict the metabolic profiles of neurons during the early stage of JEV infection. Increased glycolysis and its branched pentose phosphate pathway(PPP) flux and impaired oxidative phosphorylation(OXPHOS) in glucose utilization,and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons. Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indispensable role in maintaining the optimal propagation of JEV. In addition, analysis of metabolomic-transcriptomic regulatory network showed the pivotal biological function of lipid metabolism during JEV infection. Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis.These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.
基金the National Natural Science Foundation of China(No.82072268)the University supporting grants(Nos.2018JSTS03 and 2020SWAQ09)the Open Fund of the State Key Laboratory of Pathogenic Microbial Biosafety(No.SKLPBS1834)。
文摘Crimean-Congo hemorrhagic fever virus(CCHFV)is regarded as one of the most deadly viruses,with mortality of up to 40%.Currently,no licensed vaccine with validated efficacy against CCHFV is available.CCHFV uses Gn and Gc glycoproteins to bind and penetrate the cell,like other bunyaviruses(Hulswit et al.,2021).Thus,the desired vaccines are needed,to elicit a potent neutralizing antibody(NAb)response to counteract this process.
文摘Correction to:Virologica Sinica https://doi.org/10.1007/s12250-021-00445-0 In the original version of this article,one image in Fig.4 was accidently duplicated during figure layout and the dilution rate was mislabeled.
基金This project is financially supported by the National Key R&D Program of China(2020YFB2009002)the Program for Innovation Team of Shaanxi Province(2021TD-23).
文摘Due to the overlapping epidemiology and clinical manifestations of flaviviruses,differential diagnosis of these viral diseases is complicated,and the results are unreliable.There is perpetual demand for a simplified,sensitive,rapid and inexpensive assay with less cross-reactivity.The ability to sort distinct virus particles from a mixture of biological samples is crucial for improving the sensitivity of diagnoses.Therefore,we developed a sorting system for the subsequent differential diagnosis of dengue and tick-borne encephalitis in the early stage.We employed aptamer-modified polystyrene(PS)microspheres with different diameters to specifically capture dengue virus(DENV)and tick-borne encephalitis virus(TBEV),and utilized a traveling surface acoustic wave(TSAW)device to accomplish microsphere sorting according to particle size.The captured viruses were then characterized by laser scanning confocal microscopy(LSCM),field emission scanning electron microscopy(FE-SEM)and reverse transcription-polymerase chain reaction(RT‒PCR).The characterization results indicated that the acoustic sorting process was effective and damage-free for subsequent analysis.Furthermore,the strategy can be utilized for sample pretreatment in the differential diagnosis of viral diseases.
