Turnip mosaic virus(TuMV)is a devastating potyvirus pathogen that infects a wide variety of both cultivated and wild Brassicaceae plants.We urgently need more information and understanding of TuMV pathogenesis and the...Turnip mosaic virus(TuMV)is a devastating potyvirus pathogen that infects a wide variety of both cultivated and wild Brassicaceae plants.We urgently need more information and understanding of TuMV pathogenesis and the host responses involved in disease development in cruciferous crops.TuMV displays great versatility in viral pathogenesis,especially in its replication and intercellular movement.Moreover,in the coevolutionary arms races between TuMV and its hosts,the virus has evolved to co-opt host factors to facilitate its infection and counter host defense responses.This review mainly focuses on recent advances in understanding the viral factors that contribute to the TuMV infection cycle and the host resistance mechanism in Brassica.Finally,we propose some future research directions on TuMV pathogenesis and control strategies to design durable TuMV-resistant Brassica crops.展开更多
If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Corona...If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Coronavirus 2(SARS-CoV-2)be better understood,as well as the downstream severe or lethal clinical complications.While the identification of notable comorbidities has now helped to define broad risk groups,the idiosyncratic responses of individual patients can generate unexpected clinical deterioration that is difficult to predict from initial clinical features.Thus,physicians caring for patients with COVID-19 face clinical dilemmas on a daily basis.The ability to decipher individual predispositions to SARS-CoV-2 infection or severe illness,in light of variations in host immunological and inflammatory responses,in particular as a result of genetic variations,would be of great benefit in infection management.To this end,this work associates the description of COVID-19 clinical complications,comorbidities,sequelae,and environmental and genetic factors.We also give examples of underlying genomic susceptibility to COVID-19,especially with regard to the newly reported link between the disease and the unbalanced formation of neutrophil extracellular traps.As a consequence,we propose that the host/genetic factors associated with COVID-19 call for precision medicine in its treatment.This is to our knowledge the first article describing elements towards precision medicine for patients with COVID-19.展开更多
A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typ...A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typing technologies, which are now commercially available, accom-panied by statistical methods to identify host genetic factors that are associated with target diseases or complex genetic traits. One of the most striking features of the GWAS strategy is the ability to identify unexpected disease-associated genetic markers across the entire human genome. Here, we describe the technological aspects of the GWAS strategy with examples from actual GWAS reports related to hepatitis research, including drug response for patients with chronic hepatitis C, susceptibility to primary biliary cirrhosis, and hepatitis-B-related hepatocellular carcinoma.展开更多
Enteroviruses(EVs)are human pathogens commonly observed in children aged 0–5 years and adults.EV infections usually cause the common cold and hand-foot-and-mouth disease;however,more severe infections can result in m...Enteroviruses(EVs)are human pathogens commonly observed in children aged 0–5 years and adults.EV infections usually cause the common cold and hand-foot-and-mouth disease;however,more severe infections can result in multiorgan complications,such as polio,aseptic meningitis,and myocarditis.The molecular mechanisms by which enteroviruses cause these diseases are still poorly understood,but accumulating evidence points to two enterovirus proteases,2Apro and 3Cpro,as the key players in pathogenesis.The 2Apro performs post-translational proteolytic processing of viral polyproteins and cleaves several host factors to evade antiviral immune responses and promote viral replication.It was also discovered that coxsackievirus-induced cardiomyopathy was caused by 2Apro-mediated cleavage of dystrophin in cardiomyocytes,indicating that cellular protein proteolysis may play a key role in enterovirus-associated diseases.Therefore,studies of 2Apro could reveal additional substrates that may be associated with specific diseases.Here,we discuss the genetic and structural properties of 2Apro and review how the protease antagonizes innate immune responses to promote viral replication,as well as novel substrates and mechanisms for 2Apro.We also summarize the current approaches for identifying the substrates of 2Apro to discover novel mechanisms relating to certain diseases.展开更多
Severe fever with thrombocytopenia syndrome virus(SFTSV)is a highly pathogenic tick-borne bunyavirus that causes lethal infectious disease and severe fever with thrombocytopenia syndrome(SFTS)in humans.The molecular m...Severe fever with thrombocytopenia syndrome virus(SFTSV)is a highly pathogenic tick-borne bunyavirus that causes lethal infectious disease and severe fever with thrombocytopenia syndrome(SFTS)in humans.The molecular mechanisms and host cellular factors required for SFTSV infection remain uncharacterized.Using a genome-wide CRISPR-based screening strategy,we identified a host cellular protein,sorting nexin 11(SNX11)which is involved in the intracellular endosomal trafficking pathway,as an essential cell factor for SFTSV infection.An SNX11-KO HeLa cell line was established,and SFTSV replication was significantly reduced.The glycoproteins of SFTSV were detected and remained in later endosomal compartments but were not detectable in the endoplasmic reticulum(ER)or Golgi apparatus.pH values in the endosomal compartments of the SNX11-KO cells increased compared with the pH of normal HeLa cells,and lysosomal-associated membrane protein 1(LAMP1)expression was significantly elevated in the SNX11-KO cells.Overall,these results indicated that penetration of SFTSV from the endolysosomes into the cytoplasm of host cells was blocked in the cells lacking SNX11.Our study for the first time provides insight into the important role of the SNX11 as an essential host factor in the intracellular trafficking and penetrating process of SFTSV infection via potential regulation of viral protein sorting,membrane fusion,and other endocytic machinery.展开更多
In this study,SB216763 and cyclosporine A were identified as anti-influenza A virus(IAV)agents by tran-scriptome signature reversion(TSR)analysis through deep mining of the cellular transcriptome of hu-man airway and ...In this study,SB216763 and cyclosporine A were identified as anti-influenza A virus(IAV)agents by tran-scriptome signature reversion(TSR)analysis through deep mining of the cellular transcriptome of hu-man airway and lung cell lines infected with 3 strains of IAV and the chemical perturbations library.A synergistic effect of SB216763 and cyclosporine A against influenza A was disclosed by quantification of the network-based relationship,which was validated in vitro.Along with burgeoning omics approaches,transcriptome-based drug development is flourishing,which provides a novel insight into antivirals dis-covery with comprehensive cellular transcriptional information of disease and chemical perturbations in multicomponent intervention.This strategy can be applied as a new approach in discovering multitar-get antiviral agents from approved drugs,clinical compounds,natural products or other known bioactive compounds.展开更多
APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting ...APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting the antiviral activity of A3G.Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development.Currently,there is an urgent need for understanding the three dimensional structure of full-length A3G.In this work,we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2(APO2)and the catalytic domain structure of A3G.Two compounds,IMB26 and IMB35,which have been shown to bind to A3G and block degradation by Vif,were docked into the A3G model and the binding modes were generated for further analysis.The results may be used to design or optimize molecules targeting Vif–A3G interaction,and lead to the development of novel anti-HIV drugs.展开更多
基金supported by a grant from Chinese Agriculture Research System of MOF and MARA (Grant No.CARS-24-C-04)Zhejiang Provincial Natural Science Foundation (Grant No.LZ24C140001)+1 种基金National Natural Science Foundation of China (Grant Nos.32370144,32070165)the K.C.Wong Magna Fund in Ningbo University。
文摘Turnip mosaic virus(TuMV)is a devastating potyvirus pathogen that infects a wide variety of both cultivated and wild Brassicaceae plants.We urgently need more information and understanding of TuMV pathogenesis and the host responses involved in disease development in cruciferous crops.TuMV displays great versatility in viral pathogenesis,especially in its replication and intercellular movement.Moreover,in the coevolutionary arms races between TuMV and its hosts,the virus has evolved to co-opt host factors to facilitate its infection and counter host defense responses.This review mainly focuses on recent advances in understanding the viral factors that contribute to the TuMV infection cycle and the host resistance mechanism in Brassica.Finally,we propose some future research directions on TuMV pathogenesis and control strategies to design durable TuMV-resistant Brassica crops.
基金The author thanks S.Dejasse,C.McCarthy,M.Ychou,and RC Gallo.A.R.Thierry is supported by INSERM.This work was funded by the SIRIC Montpellier Cancer Grant(No.INCa Inserm DGOS 12553).
文摘If the current rate of infection are to be better managed,and future waves of infection kept at bay,it is absolutely necessary that the conditions and mechanisms of exposure to Severe Acute Respiratory Syndrome-Coronavirus 2(SARS-CoV-2)be better understood,as well as the downstream severe or lethal clinical complications.While the identification of notable comorbidities has now helped to define broad risk groups,the idiosyncratic responses of individual patients can generate unexpected clinical deterioration that is difficult to predict from initial clinical features.Thus,physicians caring for patients with COVID-19 face clinical dilemmas on a daily basis.The ability to decipher individual predispositions to SARS-CoV-2 infection or severe illness,in light of variations in host immunological and inflammatory responses,in particular as a result of genetic variations,would be of great benefit in infection management.To this end,this work associates the description of COVID-19 clinical complications,comorbidities,sequelae,and environmental and genetic factors.We also give examples of underlying genomic susceptibility to COVID-19,especially with regard to the newly reported link between the disease and the unbalanced formation of neutrophil extracellular traps.As a consequence,we propose that the host/genetic factors associated with COVID-19 call for precision medicine in its treatment.This is to our knowledge the first article describing elements towards precision medicine for patients with COVID-19.
文摘A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typing technologies, which are now commercially available, accom-panied by statistical methods to identify host genetic factors that are associated with target diseases or complex genetic traits. One of the most striking features of the GWAS strategy is the ability to identify unexpected disease-associated genetic markers across the entire human genome. Here, we describe the technological aspects of the GWAS strategy with examples from actual GWAS reports related to hepatitis research, including drug response for patients with chronic hepatitis C, susceptibility to primary biliary cirrhosis, and hepatitis-B-related hepatocellular carcinoma.
基金supported by the National Key Research and Development Program of China (Project No.2021YFC2302003).
文摘Enteroviruses(EVs)are human pathogens commonly observed in children aged 0–5 years and adults.EV infections usually cause the common cold and hand-foot-and-mouth disease;however,more severe infections can result in multiorgan complications,such as polio,aseptic meningitis,and myocarditis.The molecular mechanisms by which enteroviruses cause these diseases are still poorly understood,but accumulating evidence points to two enterovirus proteases,2Apro and 3Cpro,as the key players in pathogenesis.The 2Apro performs post-translational proteolytic processing of viral polyproteins and cleaves several host factors to evade antiviral immune responses and promote viral replication.It was also discovered that coxsackievirus-induced cardiomyopathy was caused by 2Apro-mediated cleavage of dystrophin in cardiomyocytes,indicating that cellular protein proteolysis may play a key role in enterovirus-associated diseases.Therefore,studies of 2Apro could reveal additional substrates that may be associated with specific diseases.Here,we discuss the genetic and structural properties of 2Apro and review how the protease antagonizes innate immune responses to promote viral replication,as well as novel substrates and mechanisms for 2Apro.We also summarize the current approaches for identifying the substrates of 2Apro to discover novel mechanisms relating to certain diseases.
基金supported by the National Key Project for Infectious Disease from the Ministry of Science and Technology (Grant No. 2018ZX10711-001)
文摘Severe fever with thrombocytopenia syndrome virus(SFTSV)is a highly pathogenic tick-borne bunyavirus that causes lethal infectious disease and severe fever with thrombocytopenia syndrome(SFTS)in humans.The molecular mechanisms and host cellular factors required for SFTSV infection remain uncharacterized.Using a genome-wide CRISPR-based screening strategy,we identified a host cellular protein,sorting nexin 11(SNX11)which is involved in the intracellular endosomal trafficking pathway,as an essential cell factor for SFTSV infection.An SNX11-KO HeLa cell line was established,and SFTSV replication was significantly reduced.The glycoproteins of SFTSV were detected and remained in later endosomal compartments but were not detectable in the endoplasmic reticulum(ER)or Golgi apparatus.pH values in the endosomal compartments of the SNX11-KO cells increased compared with the pH of normal HeLa cells,and lysosomal-associated membrane protein 1(LAMP1)expression was significantly elevated in the SNX11-KO cells.Overall,these results indicated that penetration of SFTSV from the endolysosomes into the cytoplasm of host cells was blocked in the cells lacking SNX11.Our study for the first time provides insight into the important role of the SNX11 as an essential host factor in the intracellular trafficking and penetrating process of SFTSV infection via potential regulation of viral protein sorting,membrane fusion,and other endocytic machinery.
基金supported by the CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-028 and 2020I2M-2-010)the Opening Foundation of the State Key Laboratory of Bioactive Substance and Function of Natural Medicines (No. GTZK202109)+2 种基金the National Natural Science Foundation of China (No. 81473256)the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (No. BZ0150)the Disciplines Construction Project (No. 201920200802)
文摘In this study,SB216763 and cyclosporine A were identified as anti-influenza A virus(IAV)agents by tran-scriptome signature reversion(TSR)analysis through deep mining of the cellular transcriptome of hu-man airway and lung cell lines infected with 3 strains of IAV and the chemical perturbations library.A synergistic effect of SB216763 and cyclosporine A against influenza A was disclosed by quantification of the network-based relationship,which was validated in vitro.Along with burgeoning omics approaches,transcriptome-based drug development is flourishing,which provides a novel insight into antivirals dis-covery with comprehensive cellular transcriptional information of disease and chemical perturbations in multicomponent intervention.This strategy can be applied as a new approach in discovering multitar-get antiviral agents from approved drugs,clinical compounds,natural products or other known bioactive compounds.
基金part by 973 program(2012C B911102)the National S&T Major Special Project on Major New Drug Innovation(2012ZX09102101-018)the National S&T International Collaboration 2010DFA31580(J.D.J.)and 2010DFB30870(Q.J.).
文摘APOBEC3G(A3G)is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication.The virally encoded protein Vif binds to A3G and induces its degradation,thereby counteracting the antiviral activity of A3G.Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development.Currently,there is an urgent need for understanding the three dimensional structure of full-length A3G.In this work,we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2(APO2)and the catalytic domain structure of A3G.Two compounds,IMB26 and IMB35,which have been shown to bind to A3G and block degradation by Vif,were docked into the A3G model and the binding modes were generated for further analysis.The results may be used to design or optimize molecules targeting Vif–A3G interaction,and lead to the development of novel anti-HIV drugs.