The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus(HCV) infection. In patients,the outcome is determined by a series of complex host-virus interactions,whether it is a n...The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus(HCV) infection. In patients,the outcome is determined by a series of complex host-virus interactions,whether it is a natural infection or results from clinical intervention. Strong and persistent CD8+ and CD4+ T-cell responses are critical in HCV clearance,as well as cytokineinduced factors that can directly inhibit virus replication. Newly available direct-acting antivirals(DAAs) are very effective in viral clearance in patients. DAA treatment may further result in the down-regulation of programmed death-1,leading to rapid restoration of HCV-specific CD8+ T cell functions. In this review,we focus on recent studies that address the host responses critical for viral clearance and disease resolution. Additional discussion is devoted to the prophylactic vaccine development as well as to current efforts aimed at understanding the host innate responses against HCV infection. Current theories on how the ubiquitin system and interferon-stimulated genes may affect HCV replication are also discussed.展开更多
Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutr...Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.展开更多
Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I t...Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR-/-) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Re) or PD-L1 were i.p. injected. We found that CD8+ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8+ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8+ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.展开更多
Based on a 16-warm-season statistical study on the mesoscale convective systems(MCSs)that were generated over the Tibetan Plateau(TP),11 long-lived eastward propagating MCSs of the same type were selected for a compos...Based on a 16-warm-season statistical study on the mesoscale convective systems(MCSs)that were generated over the Tibetan Plateau(TP),11 long-lived eastward propagating MCSs of the same type were selected for a composite semiidealized simulation and a corresponding no-latent-heating sensitivity run by using the Weather Research and Forecasting(WRF)model.Common evolutionary features and associated mechanisms of this type of long-lived eastward propagating MCS were investigated.Main results are as follows:(i)This type of MCS was generated in a favorable background environment which was characterized by a notable upper-tropospheric divergence south of an upper-level jet,a strong warm advection around a middle-level shortwave trough’s central area,and an instable convective stratification below the trough.Development of the MCS featured rapid increase of cyclonic vorticity in the middle and lower troposphere.The convergence-related vertical stretching and tilting were key factors for the cyclonic-vorticity’s production,and convection-related upward cyclonic-vorticity transport contributed to the upward extending of the MCS.(ii)During the vacating stage of the MCS,it first coupled with a quasistationary Tibetan Plateau vortex(TPV)over the TP’s eastern section,and then decoupled from the vortex.In the former stage,the MCS contributed to maintaining ascending motions and convergence associated with the TPV,which favored its persistence;whereas,in the latter stage,decoupling weakened the TPV-associated convection significantly.This reduced the upward transport of cyclonic vorticity notably,which,together with the negative tilting effect,finally led to the vortex’s dissipation.(iii)After vacating TP,the MCS first weakened due to the disappearance of strong direct sensible heating from the TP on its bottom,and then,under the favorable conditions associated with the shortwave trough over the eastern section of the TP,the MCS redeveloped rapidly.Convergence-related cyclonic-vorticity production in the middle and lower troposphere and upward transport of cyclonic vorticity due to convection governed the MCS’s redevelopment.(iv)Sensitivity simulation shows that latent heating was a necessary condition for the formation and development of the long-lived eastward propagating MCS.On the one hand,this MCS affected the TP’s eastern section and downstream regions directly by inducing precipitation;and on the other hand,it exerted effects on the precipitation over a wider range in the downstream regions by modulating large-scale circulations over and around the TP.展开更多
The COVID-19 pandemic,caused by the highly transmissible and pathogenic severe acute respiratory syndrome coronavirus 2(SAR-CoV-2),has led to more than 2.7 million deaths worldwide as of March 2021.Although considerab...The COVID-19 pandemic,caused by the highly transmissible and pathogenic severe acute respiratory syndrome coronavirus 2(SAR-CoV-2),has led to more than 2.7 million deaths worldwide as of March 2021.Although considerable efforts are underway to reveal the immunopathology of COVID-19,the key factors and processes that initiate hyperinflammatory responses and cause severe clinical outcomes in certain individuals remain unclear.The damage-associated molecular pattern(DAMP)molecule IL-33 belongs to the IL-1 family and has been recognized as an alarmin that indicates cellular damage or infection.Full-length IL-33 requires cleavage by proteases to generate its mature bioactive form,which can bind to the ST2 receptor(also known as IL-1RL1),leading to activation of the NF-κB pathway in various innate and adaptive immune cells.The relatively high abundance of IL-33 in epithelial and endothelial cells accounts for its proinflammatory role in respiratory diseases.1 Recent observations have revealed that serum IL-33 is upregulated in elderly patients with COVID-19 and associated with adverse outcomes.展开更多
基金Supported by NIH AI109100(to Sun J),R01AI110358(to Yi M)UTMB Institute for Human Infection and Immunity and UT System Rising STAR Award(to Rajsbaum R)
文摘The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus(HCV) infection. In patients,the outcome is determined by a series of complex host-virus interactions,whether it is a natural infection or results from clinical intervention. Strong and persistent CD8+ and CD4+ T-cell responses are critical in HCV clearance,as well as cytokineinduced factors that can directly inhibit virus replication. Newly available direct-acting antivirals(DAAs) are very effective in viral clearance in patients. DAA treatment may further result in the down-regulation of programmed death-1,leading to rapid restoration of HCV-specific CD8+ T cell functions. In this review,we focus on recent studies that address the host responses critical for viral clearance and disease resolution. Additional discussion is devoted to the prophylactic vaccine development as well as to current efforts aimed at understanding the host innate responses against HCV infection. Current theories on how the ubiquitin system and interferon-stimulated genes may affect HCV replication are also discussed.
基金in part,by grants from the NIH(AI109100 and AI126371 to JS)PY was a visiting scientist partially supported by the Department of Infectious Diseases,Xiangya Hospital,China and the Natural Science Foundation of Hunan Province(no.14JJ6003)DMKY and ZK were recipients of summer internships from an NIAID T35 training grant(AI078878,PI:LS).
文摘Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.
文摘Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR-/-) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Re) or PD-L1 were i.p. injected. We found that CD8+ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8+ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8+ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.
基金This work was supported by the National Key R&D Program of China(Grant No.2018YFC1507606)the National Natural Science Foundation of China(Grant Nos.41775046,42075002,91637211,and 42030611)+1 种基金the Foundation of Heavy Rain and Drought-Flood Disasters in Plateau and Basin Key Laboratory of Sichuan Province(Grant No.SZKT202001)the Youth Innovation Promotion Association,Chinese Academy of Sciences.
文摘Based on a 16-warm-season statistical study on the mesoscale convective systems(MCSs)that were generated over the Tibetan Plateau(TP),11 long-lived eastward propagating MCSs of the same type were selected for a composite semiidealized simulation and a corresponding no-latent-heating sensitivity run by using the Weather Research and Forecasting(WRF)model.Common evolutionary features and associated mechanisms of this type of long-lived eastward propagating MCS were investigated.Main results are as follows:(i)This type of MCS was generated in a favorable background environment which was characterized by a notable upper-tropospheric divergence south of an upper-level jet,a strong warm advection around a middle-level shortwave trough’s central area,and an instable convective stratification below the trough.Development of the MCS featured rapid increase of cyclonic vorticity in the middle and lower troposphere.The convergence-related vertical stretching and tilting were key factors for the cyclonic-vorticity’s production,and convection-related upward cyclonic-vorticity transport contributed to the upward extending of the MCS.(ii)During the vacating stage of the MCS,it first coupled with a quasistationary Tibetan Plateau vortex(TPV)over the TP’s eastern section,and then decoupled from the vortex.In the former stage,the MCS contributed to maintaining ascending motions and convergence associated with the TPV,which favored its persistence;whereas,in the latter stage,decoupling weakened the TPV-associated convection significantly.This reduced the upward transport of cyclonic vorticity notably,which,together with the negative tilting effect,finally led to the vortex’s dissipation.(iii)After vacating TP,the MCS first weakened due to the disappearance of strong direct sensible heating from the TP on its bottom,and then,under the favorable conditions associated with the shortwave trough over the eastern section of the TP,the MCS redeveloped rapidly.Convergence-related cyclonic-vorticity production in the middle and lower troposphere and upward transport of cyclonic vorticity due to convection governed the MCS’s redevelopment.(iv)Sensitivity simulation shows that latent heating was a necessary condition for the formation and development of the long-lived eastward propagating MCS.On the one hand,this MCS affected the TP’s eastern section and downstream regions directly by inducing precipitation;and on the other hand,it exerted effects on the precipitation over a wider range in the downstream regions by modulating large-scale circulations over and around the TP.
基金supported by NIH grants,including EY028773 to J.S.and AI153586 to Y.L.,and the UTMB Institute of Human Infections&Immunity Pilot grant to Y.L.
文摘The COVID-19 pandemic,caused by the highly transmissible and pathogenic severe acute respiratory syndrome coronavirus 2(SAR-CoV-2),has led to more than 2.7 million deaths worldwide as of March 2021.Although considerable efforts are underway to reveal the immunopathology of COVID-19,the key factors and processes that initiate hyperinflammatory responses and cause severe clinical outcomes in certain individuals remain unclear.The damage-associated molecular pattern(DAMP)molecule IL-33 belongs to the IL-1 family and has been recognized as an alarmin that indicates cellular damage or infection.Full-length IL-33 requires cleavage by proteases to generate its mature bioactive form,which can bind to the ST2 receptor(also known as IL-1RL1),leading to activation of the NF-κB pathway in various innate and adaptive immune cells.The relatively high abundance of IL-33 in epithelial and endothelial cells accounts for its proinflammatory role in respiratory diseases.1 Recent observations have revealed that serum IL-33 is upregulated in elderly patients with COVID-19 and associated with adverse outcomes.