Influenza A virus(IAV),responsible for seasonal epidemics and recurring pandemics,represents a global threat to public health.Given the risk of a potential IAV pandemic,it is increasingly important to better understan...Influenza A virus(IAV),responsible for seasonal epidemics and recurring pandemics,represents a global threat to public health.Given the risk of a potential IAV pandemic,it is increasingly important to better understand virushost interactions and develop new anti-viral strategies.Here,we reported nonmuscle myosin IIA(MYH9)-mediated regulation of IAV infection.MYH9 depletion caused a profound inhibition of IAV infection by reducing viral attachment and internalization in human lung epithelial cells.Surprisingly,overexpression of MYH9 also led to a significant reduction in viral productive infection.Interestingly,overexpression of MYH9 retained viral attachment,internalization,or uncoating,but suppressed the viral ribonucleoprotein(vRNP)activity in a minigenome system.Further analyses found that excess MYH9 might interrupt the formation of vRNP by interacting with the viral nucleoprotein(NP)and result in the reduction of the completed vRNP in the nucleus,thereby inhibiting subsequent viral RNA transcription and replication.Together,we discovered that MYH9 can interact with IAV NP protein and engage in the regulation of vRNP complexes,thereby involving viral replication.These findings enlighten new mechanistic insights into the complicated interface of host-IAV interactions,ultimately making it an attractive target for the generation of antiviral drugs.展开更多
Dear Editor,Hepatitis C Virus(HCV)infection is a huge public health problem globally,because it can lead to adverse long-term clinical outcomes.In China,the population has experienced a skyrocketing growth of HCV infe...Dear Editor,Hepatitis C Virus(HCV)infection is a huge public health problem globally,because it can lead to adverse long-term clinical outcomes.In China,the population has experienced a skyrocketing growth of HCV infections because of paid blood donations in the late 1980s to early 1990s(Lu et al.2013;Yin et al.2015).展开更多
Background:Interferon kappa(IFN-k)is a type I interferon(IFN-I)that inhibits virus replication by evoking interferon-stimulated genes(ISGs).However,as an evolutionarily ancient interferon,IFN-k may function differentl...Background:Interferon kappa(IFN-k)is a type I interferon(IFN-I)that inhibits virus replication by evoking interferon-stimulated genes(ISGs).However,as an evolutionarily ancient interferon,IFN-k may function differently from the later emerged interferon-a and b.Methods:Conventional molecular biology methods were used to determine the localization of IFN-k and its structure and function.In addition,we employed RT-PCR,western blot,and RNA-Seq technologies to characterize the ISGs expression profile and antiviral activities exerted by IFN-k or IFN-a2.Results:Human IFN-k exists in two forms upon ectopic expression,one located on the cell membrane and the other secreted outside the cells.The membrane-anchored IFN-k showed the ability to induce ISGs and curtail RNA virus replication,whereas the secreted IFN-k failed to do so.Structural analyses indicated that 1-27aa at the N-terminus was the signal peptide,and 28-37aa was predicted as the transmembrane region.However,our data demonstrated that both of them were not associated with membrane localization of IFN-k;the former influenced the expression and secretion of IFN-k,and the latter had an impact on the induction of ISGs.In addition,prokaryotic purified soluble mature human IFN-k was also capable of inducing ISGs and inhibiting RNA virus replication.Importantly,human IFN-k induced a faster ISG response but with a lower intensity and a shorter half-life than the response of IFN-a2.In contrast,IFN-a2 started to function later but was stronger and more durable than IFN-k.Conclusions:Human IFN-k-induced ISG response and inhibited respiratory RNA virus replication dependent on cell-to-cell interactions.In addition,compared with IFN-a2,IFN-k exerted effects more rapidly in the early phase,with less intensity and a shorter half-life.Therefore,IFN-k may constitute the first line of IFN-I against respiratory virus infections.展开更多
Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical...Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies.Here,we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts.The differentially expressed genes were analyzed between long-term non-progressors,viremic non-progressors and typical progressors,and between elite controllers and non-elite controllers among the long-term nonprogressors.Several genes related to T-cell growth,proliferation and differentiation and antiapoptosis were upregulated,whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors.The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up,which included 51 genes significantly associated with slower disease progression,and 210 genes associated with aggressive disease progression.Overall,our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses.Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART,such as the administration of interleukin-7,healthy allogenic CD4^(+)T cells(providing CD4^(+)T-cell growth factors),or Tregs.展开更多
基金supported by the National Natural Science Foundation of China(82071788,81901598,81771704,and 82041015)National Key R&D Program of China(2022YFC2604100).
文摘Influenza A virus(IAV),responsible for seasonal epidemics and recurring pandemics,represents a global threat to public health.Given the risk of a potential IAV pandemic,it is increasingly important to better understand virushost interactions and develop new anti-viral strategies.Here,we reported nonmuscle myosin IIA(MYH9)-mediated regulation of IAV infection.MYH9 depletion caused a profound inhibition of IAV infection by reducing viral attachment and internalization in human lung epithelial cells.Surprisingly,overexpression of MYH9 also led to a significant reduction in viral productive infection.Interestingly,overexpression of MYH9 retained viral attachment,internalization,or uncoating,but suppressed the viral ribonucleoprotein(vRNP)activity in a minigenome system.Further analyses found that excess MYH9 might interrupt the formation of vRNP by interacting with the viral nucleoprotein(NP)and result in the reduction of the completed vRNP in the nucleus,thereby inhibiting subsequent viral RNA transcription and replication.Together,we discovered that MYH9 can interact with IAV NP protein and engage in the regulation of vRNP complexes,thereby involving viral replication.These findings enlighten new mechanistic insights into the complicated interface of host-IAV interactions,ultimately making it an attractive target for the generation of antiviral drugs.
基金supported by the National Natural Science Foundation of China(Grants 81861138003 and 81672057)。
文摘Dear Editor,Hepatitis C Virus(HCV)infection is a huge public health problem globally,because it can lead to adverse long-term clinical outcomes.In China,the population has experienced a skyrocketing growth of HCV infections because of paid blood donations in the late 1980s to early 1990s(Lu et al.2013;Yin et al.2015).
基金This work was supported by the National Science Foundation of China(No.82071788)Three-year Action Plan for Shenkang Clinical Research from Shanghai Municipal Health Commission(SHDC2020CR3011A)the Special Medical Innovation Research Project of“Scientific and Technological Innovation Action Plan”of Shanghai Municipal Commission of Science and Technology in 2020(20Y11900500).
文摘Background:Interferon kappa(IFN-k)is a type I interferon(IFN-I)that inhibits virus replication by evoking interferon-stimulated genes(ISGs).However,as an evolutionarily ancient interferon,IFN-k may function differently from the later emerged interferon-a and b.Methods:Conventional molecular biology methods were used to determine the localization of IFN-k and its structure and function.In addition,we employed RT-PCR,western blot,and RNA-Seq technologies to characterize the ISGs expression profile and antiviral activities exerted by IFN-k or IFN-a2.Results:Human IFN-k exists in two forms upon ectopic expression,one located on the cell membrane and the other secreted outside the cells.The membrane-anchored IFN-k showed the ability to induce ISGs and curtail RNA virus replication,whereas the secreted IFN-k failed to do so.Structural analyses indicated that 1-27aa at the N-terminus was the signal peptide,and 28-37aa was predicted as the transmembrane region.However,our data demonstrated that both of them were not associated with membrane localization of IFN-k;the former influenced the expression and secretion of IFN-k,and the latter had an impact on the induction of ISGs.In addition,prokaryotic purified soluble mature human IFN-k was also capable of inducing ISGs and inhibiting RNA virus replication.Importantly,human IFN-k induced a faster ISG response but with a lower intensity and a shorter half-life than the response of IFN-a2.In contrast,IFN-a2 started to function later but was stronger and more durable than IFN-k.Conclusions:Human IFN-k-induced ISG response and inhibited respiratory RNA virus replication dependent on cell-to-cell interactions.In addition,compared with IFN-a2,IFN-k exerted effects more rapidly in the early phase,with less intensity and a shorter half-life.Therefore,IFN-k may constitute the first line of IFN-I against respiratory virus infections.
基金This work was supported by the National Grand Program on Key Infectious Disease Control(No.2017ZX10202102)the National Nature Science Foundation of China(No.81561128008).
文摘Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies.Here,we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts.The differentially expressed genes were analyzed between long-term non-progressors,viremic non-progressors and typical progressors,and between elite controllers and non-elite controllers among the long-term nonprogressors.Several genes related to T-cell growth,proliferation and differentiation and antiapoptosis were upregulated,whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors.The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up,which included 51 genes significantly associated with slower disease progression,and 210 genes associated with aggressive disease progression.Overall,our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses.Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART,such as the administration of interleukin-7,healthy allogenic CD4^(+)T cells(providing CD4^(+)T-cell growth factors),or Tregs.
