Severe influenza infections are often associated with the excessive induction of pro-inflammatory cytokines,which is also referred to as"cytokine storms".Several studies have shown that cytokine storms are d...Severe influenza infections are often associated with the excessive induction of pro-inflammatory cytokines,which is also referred to as"cytokine storms".Several studies have shown that cytokine storms are directly associated with influenzainduced fatal acute lung injury and acute respiratory distress syndrome.Due to the narrow administration window,current antiviral therapies are often inadequate.The efforts to use immunomodulatory agents alone or in combination with antiviral agents in the treatment of influenza in animal models have resulted in the achievement of protective effects accompanied with reduced cytokine production.Currently,there are no immunomodulatory drugs for influenza available for clinical use.Animal models,despite being ideal to study the anti-inflammatory responses to influenza virus infection,are very costly and time-consuming.Therefore,there is an urgent need to establish fast and economical screening methods using cellbased models to screen and develop novel immunomodulatory agents.In this study,we screened seven human cell lines and found that the human monocytic cell U937 supports the replication of different subtypes of influenza viruses as well as the production of the important pro-inflammatory cytokines and was selected to develop the cell-based model.The U937 cell model was validated by testing a panel of known antiviral and immunomodulatory agents and screening a drug library consisting of 1280 compounds comprised mostly of FDA-approved drugs.We demonstrated that the U937 cell model is robust and suitable for the high-throughput screening of immunomodulators and antivirals against influenza infection.展开更多
Similar to Hepatitis C virus (HCV) infection in humans, HCVcc infection can also result in persistent and chronic infection. The core protein is a variable protein and exists in several sizes. Some sizes of core prote...Similar to Hepatitis C virus (HCV) infection in humans, HCVcc infection can also result in persistent and chronic infection. The core protein is a variable protein and exists in several sizes. Some sizes of core proteins have been reported to be related to chronic HCV infection. To study the possible role of the core protein in persistent HCV infection, a persistent HCVcc infection was established, and the expression of the core protein was analysed over the course of the infection. The results show that there are three sizes of core proteins (p24, p21 and p19) expressed during the establishment of persistent HCVcc infection. Of these, the p21 core protein is the mature form of the HCV core protein. The p24 core protein is the phosphorylated form of p21. The p19 core protein appears to be a functional by-product generated during the course of infection. These three core proteins are all localized in the cytoplasm and can be encapsidated into the HCV virion. The appearance of the p19 and p24 core proteins might be related to acute HCVcc infection and chronic infection respectively and may play an important role in the pathology of a HCV infection.展开更多
Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding t...Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control.Here,we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α(HIF-1α)play key roles in the virus infection and pro-inflammatory responses.展开更多
Viral infection in respiratory tract usually leads to cell death,impairing respiratory function to cause severe disease.However,the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity...Viral infection in respiratory tract usually leads to cell death,impairing respiratory function to cause severe disease.However,the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention,and especially the high-frequency asymptomatic infection increases the risk of virus transmission.Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection.Here,we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein.We found SARS-CoV-2 virus-like particles(trVLP)suppressed cell apoptosis,but the trVLP lacking N protein didn’t.Further study verified that N protein repressed cell apoptosis in cultured cells,human lung organoids and mice.Mechanistically,N protein specifically interacted with anti-apoptotic protein MCL-1,and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1,which stabilized this protein and promoted it to hijack Bak in mitochondria.Importantly,N protein promoted the replications of IAV,DENV and ZIKV,and exacerbated death of IAV-infected mice,all of which could be blocked by a MCL-1 specific inhibitor,S63845.Altogether,we identifed a distinct anti-apoptotic function of the N protein,through which it promoted viral replication.These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction,and indicate a risk of enhanced coinfection with other viruses.We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.展开更多
基金supported by the Important Hubei Science and Technology Innovation Plan 2015ACA062 (to Xulin Chen)the Natural Science Foundation of Hubei Province (2018CFB244, to Jungang Chen)
文摘Severe influenza infections are often associated with the excessive induction of pro-inflammatory cytokines,which is also referred to as"cytokine storms".Several studies have shown that cytokine storms are directly associated with influenzainduced fatal acute lung injury and acute respiratory distress syndrome.Due to the narrow administration window,current antiviral therapies are often inadequate.The efforts to use immunomodulatory agents alone or in combination with antiviral agents in the treatment of influenza in animal models have resulted in the achievement of protective effects accompanied with reduced cytokine production.Currently,there are no immunomodulatory drugs for influenza available for clinical use.Animal models,despite being ideal to study the anti-inflammatory responses to influenza virus infection,are very costly and time-consuming.Therefore,there is an urgent need to establish fast and economical screening methods using cellbased models to screen and develop novel immunomodulatory agents.In this study,we screened seven human cell lines and found that the human monocytic cell U937 supports the replication of different subtypes of influenza viruses as well as the production of the important pro-inflammatory cytokines and was selected to develop the cell-based model.The U937 cell model was validated by testing a panel of known antiviral and immunomodulatory agents and screening a drug library consisting of 1280 compounds comprised mostly of FDA-approved drugs.We demonstrated that the U937 cell model is robust and suitable for the high-throughput screening of immunomodulators and antivirals against influenza infection.
基金funded by the National Basic Research Program of China (2009CB522504)
文摘Similar to Hepatitis C virus (HCV) infection in humans, HCVcc infection can also result in persistent and chronic infection. The core protein is a variable protein and exists in several sizes. Some sizes of core proteins have been reported to be related to chronic HCV infection. To study the possible role of the core protein in persistent HCV infection, a persistent HCVcc infection was established, and the expression of the core protein was analysed over the course of the infection. The results show that there are three sizes of core proteins (p24, p21 and p19) expressed during the establishment of persistent HCVcc infection. Of these, the p21 core protein is the mature form of the HCV core protein. The p24 core protein is the phosphorylated form of p21. The p19 core protein appears to be a functional by-product generated during the course of infection. These three core proteins are all localized in the cytoplasm and can be encapsidated into the HCV virion. The appearance of the p19 and p24 core proteins might be related to acute HCVcc infection and chronic infection respectively and may play an important role in the pathology of a HCV infection.
基金This work was supported by the National Natural Science Foundation of China(81730061,81471942,and 32070148)Guangdong Province"Pearl River Talent Plan"Innovation and Entrepreneurship Team Project(2017ZT07Y580).
文摘Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a major pathological feature of Coronavirus Disease 2019(COVID-19)and a crucial determinant in COVID-19 prognosis.Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control.Here,we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α(HIF-1α)play key roles in the virus infection and pro-inflammatory responses.
基金supported by the National Natural Science Foundation of China(81730061 to J.W.,82072834 to X.C.,32100697 to L.Z.and 32200117 to P.P.)China Postdoctoral Science Foundation(2020M683177 to P.P.,2020T130046ZX to P.P.)+2 种基金Open Research Fund Program of the State Key Laboratory of Virology of China(2021KF003 to P.P.)Open Research Fund Program of Guangdong Provincial Key Laboratory of Virology(2022KF003 to P.P.)R&D Program of Guangzhou Laboratory(SRPG22-006 to Q.Z.)。
文摘Viral infection in respiratory tract usually leads to cell death,impairing respiratory function to cause severe disease.However,the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention,and especially the high-frequency asymptomatic infection increases the risk of virus transmission.Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection.Here,we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein.We found SARS-CoV-2 virus-like particles(trVLP)suppressed cell apoptosis,but the trVLP lacking N protein didn’t.Further study verified that N protein repressed cell apoptosis in cultured cells,human lung organoids and mice.Mechanistically,N protein specifically interacted with anti-apoptotic protein MCL-1,and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1,which stabilized this protein and promoted it to hijack Bak in mitochondria.Importantly,N protein promoted the replications of IAV,DENV and ZIKV,and exacerbated death of IAV-infected mice,all of which could be blocked by a MCL-1 specific inhibitor,S63845.Altogether,we identifed a distinct anti-apoptotic function of the N protein,through which it promoted viral replication.These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction,and indicate a risk of enhanced coinfection with other viruses.We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.
