丙型肝炎(丙肝)病毒(hepatitis C virus,HCV)可以通过几种途径影响宿主免疫功能,使病毒在宿主细胞内持续复制,最终导致HCV慢性感染。目前治疗慢性丙肝的方法主要是聚乙二醇干扰素和利巴韦林联合用法,此种疗法在HCV1型患者中约50%不能产...丙型肝炎(丙肝)病毒(hepatitis C virus,HCV)可以通过几种途径影响宿主免疫功能,使病毒在宿主细胞内持续复制,最终导致HCV慢性感染。目前治疗慢性丙肝的方法主要是聚乙二醇干扰素和利巴韦林联合用法,此种疗法在HCV1型患者中约50%不能产生持续病毒学应答,且有不良反应。近年来,随着对HCV复制以及病毒非结构蛋白功能的深入研究,针对减少HCV载量的特异性药物的研发取得了较大进展。本文就HCV的细胞入侵、复制、逃避宿主的固有和获得性免疫及抗HCV临床试验药物的最新进展进行综述。展开更多
Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seaso...Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of the pandemic coronavirus disease 2019(COVID-19),which threatens human health and public safety.In the urgent campaign to develop ant...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of the pandemic coronavirus disease 2019(COVID-19),which threatens human health and public safety.In the urgent campaign to develop anti-S ARS-CoV-2 therapies,the initial entry step is one of the most appealing targets.In this review,we summarize the current understanding of SARS-CoV-2 cell entry,and the development of targeted antiviral strategies.Moreover,we speculate upon future directions toward nextgeneration of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.展开更多
Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimate...Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 （PC1）, a large multi-functional memb-rane receptor protein able to regulate ion channel complexes, whereas polycystin-2 （PC2）, encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum （ER）. In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this feld could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.展开更多
Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor...Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus （HCV） infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.展开更多
Viruses in the family Reoviridae are non-enveloped particles comprising a segmented double-stranded RNA genome surrounded by a two-layered or multi-layered icosahedral protein capsid.These viruses are classified into ...Viruses in the family Reoviridae are non-enveloped particles comprising a segmented double-stranded RNA genome surrounded by a two-layered or multi-layered icosahedral protein capsid.These viruses are classified into two sub-families based on their particle structural organization.Recent studies have focused on high-resolution three-dimensional structures of reovirus particles by using cryo-electron microscopy (cryo-EM) to approach the resolutions seen in X-ray crystallographic structures.The results of cryo-EM image reconstructions allow tracing of most of the protein side chains,and thus permit integration of structural and functional information into a coherent mechanism for reovirus assembly and entry.展开更多
Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous vir...Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodiesfor control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.展开更多
The surface glycoproteins of coronaviruses play an important role in receptor binding and cell entry. Different coronaviruses interact with their specific receptors to enter host cells. Lentiviruses pseudotyped with t...The surface glycoproteins of coronaviruses play an important role in receptor binding and cell entry. Different coronaviruses interact with their specific receptors to enter host cells. Lentiviruses pseudotyped with their spike proteins(S) were compared to analyze the entry efficiency of various coronaviruses. Our results indicated that S proteins from different coronaviruses displayed varied abilities to mediate pseudotyped virus infection. Furthermore, the cell tropisms of porcine epidemic diarrhea virus(PEDV) and transmissible gastroenteritis virus(TGEV) have been characterized by live and pseudotyped viruses. Both live and pseudoviruses could infected VeroCCL-81(monkey kidney), Huh-7(human liver), and PK-15(pig kidney) cells efficiently. CCL94(cat kidney) cells could be infected efficiently by TGEV but not PEDV. Overall, our study provides new insights into the mechanisms of viral entry and forms a basis for antiviral drug screening.展开更多
Grass carp reovirus(GCRV),the genus Aquareovirus in family Reoviridae,is viewed as the most pathogenic aquareovirus.To understand the molecular mechanism of how aquareovirus initiates productive infection,the roles of...Grass carp reovirus(GCRV),the genus Aquareovirus in family Reoviridae,is viewed as the most pathogenic aquareovirus.To understand the molecular mechanism of how aquareovirus initiates productive infection,the roles of endosome and microtubule in cell entry of GCRV are investigated by using quantum dots(QDs)-tracking in combination with biochemical approaches.We found that GCRV infection and viral protein synthesis were significantly inhibited by pretreating host cells with endosome acidification inhibitors NH4Cl,chloroquine and bafilomycin A1(Bafi).Confocal images indicated that GCRV particles could colocalize with Rab5,Rab7 and lysosomes in host cells.Further ultrastructural examination validated that viral particle was found in late endosomes.Moreover,disruption of microtubules with nocodazole clearly blocked GCRV entry,while no inhibitory effects were observed with cytochalasin D treated cells in viral infection,hinting that intracellular transportation of endocytic uptake in GCRV infected cells is via microtubules but not actin filament.Notably,viral particles were observed to transport along microtubules by using QD-labeled GCRV.Altogether,our results suggest that GCRV can use endosomes and microtubules to initiate productive infection.展开更多
Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. We aimed to review this...Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. We aimed to review this relation in a concise way. This review article includes a large number of patients from both western and eastern countries with no clear difference of liver affection. The more severe and frequent liver injury, the more severe COVID-19 infection. Up to half of patients developed hepatitis with serum ALT elevation. Both hepatocellular and/or ductular injury were observed as evidenced by alkaline phosphatase elevation. Increase incidence of morbidity and mortality had been recorded in patients with CLD. Cirrhosis mortality extended in line with the Child-Turcotte-Pugh class. The incidence of ACLF in CLD patients with COVID 19 is not clear. There are no significant associations with the etiology of liver disease and death in cirrhosis. COVID-19 hinders HCV elimination by 2030. Patients should continue their medications if already receiving treatment. Patients with occult or resolved HBV and COVID-19 who are receiving immunosuppressive agents should use antiviral therapy to prevent viral flare-ups.展开更多
Since the beginning of the COVID-19 pandemic,multiple SARS-CoV-2 variants have emerged.While some variants spread only locally,others,referred to as variants of concern,disseminated globally and became drivers of the ...Since the beginning of the COVID-19 pandemic,multiple SARS-CoV-2 variants have emerged.While some variants spread only locally,others,referred to as variants of concern,disseminated globally and became drivers of the pandemic.All SARS-CoV-2 variants harbor mutations relative to the virus circulating early in the pandemic,and mutations in the viral spike(S)protein are considered of particular relevance since the S protein mediates host cell entry and constitutes the key target of the neutralizing antibody response.As a consequence,mutations in the S protein may increase SARS-CoV-2 infectivity and enable its evasion of neutralizing antibodies.Furthermore,mutations in the S protein can modulate viral transmissibility and pathogenicity.展开更多
Ebola virus(EBOV)is one of the most pathogenic viruses in humans which can cause a lethal hemorrhagic fever.Understanding the cellular entry mechanisms of EBOV can promote the development of new therapeutic strategies...Ebola virus(EBOV)is one of the most pathogenic viruses in humans which can cause a lethal hemorrhagic fever.Understanding the cellular entry mechanisms of EBOV can promote the development of new therapeutic strategies to control virus replication and spread.It has been known that EBOV virions bind to factors expressed at the host cell surface.Subsequently,the virions are internalized by a macropinocytosis-like process,followed by being trafficked through early and late endosomes.Recent researches indicate that the entry of EBOV into cells requires integrated and functional lipid rafts.Whilst lipid rafts have been hypothesized to play a role in virus entry,there is a current lack of supporting data.One major technical hurdle is the lack of effective approaches for observing viral entry.To provide evidence on the involvement of lipid rafts in the entry process of EBOV,we generated the fluorescently labeled Ebola virus like particles(VLPs),and utilized single-particle tracking(SPT)to visualize the entry of fluorescent Ebola VLPs in live cells and the interaction of Ebola VLPs with lipid rafts.In this study,we demonstrate the compartmentalization of Ebola VLPs in lipid rafts during entry process,and inform the essential function of lipid rafts for the entry of Ebola virus.As such,our study provides evidence to show that the raft integrity is critical for Ebola virus pathogenesis and that lipid rafts can serve as potential targets for the development of novel therapeutic strategies.展开更多
文摘丙型肝炎(丙肝)病毒(hepatitis C virus,HCV)可以通过几种途径影响宿主免疫功能,使病毒在宿主细胞内持续复制,最终导致HCV慢性感染。目前治疗慢性丙肝的方法主要是聚乙二醇干扰素和利巴韦林联合用法,此种疗法在HCV1型患者中约50%不能产生持续病毒学应答,且有不良反应。近年来,随着对HCV复制以及病毒非结构蛋白功能的深入研究,针对减少HCV载量的特异性药物的研发取得了较大进展。本文就HCV的细胞入侵、复制、逃避宿主的固有和获得性免疫及抗HCV临床试验药物的最新进展进行综述。
基金supported by the National Natural Science Foundation of China (81788101, 81573587 and 81490531)the Ministry of Science and Technology of China (2015CB5534/6)+3 种基金111 project (B08007)the Peking Union Medical College Youth FundFundamental Research Funds for Central Universities (3332013132)the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-009)
文摘Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
基金supported by the Drug Innovation Major Project(No.2018ZX09711001,China)Shandong Provincial Natural Science Foundation,China(No.ZR2020MH383)Qingdao Social Benefiting Technology Program,China(No.21-1-4-rkjk15-nsh)。
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of the pandemic coronavirus disease 2019(COVID-19),which threatens human health and public safety.In the urgent campaign to develop anti-S ARS-CoV-2 therapies,the initial entry step is one of the most appealing targets.In this review,we summarize the current understanding of SARS-CoV-2 cell entry,and the development of targeted antiviral strategies.Moreover,we speculate upon future directions toward nextgeneration of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.
基金Supported by University of Ferrara local funds:FAR 2012,2013,2014 and Regione Emilia Romagna grant(Ricerca Regione-Università)2007-2009
文摘Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 （PC1）, a large multi-functional memb-rane receptor protein able to regulate ion channel complexes, whereas polycystin-2 （PC2）, encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum （ER）. In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this feld could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.
文摘Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus （HCV） infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.
基金supported by grants from the National Natural Science Foundation of China(31172434,31372565)
文摘Viruses in the family Reoviridae are non-enveloped particles comprising a segmented double-stranded RNA genome surrounded by a two-layered or multi-layered icosahedral protein capsid.These viruses are classified into two sub-families based on their particle structural organization.Recent studies have focused on high-resolution three-dimensional structures of reovirus particles by using cryo-electron microscopy (cryo-EM) to approach the resolutions seen in X-ray crystallographic structures.The results of cryo-EM image reconstructions allow tracing of most of the protein side chains,and thus permit integration of structural and functional information into a coherent mechanism for reovirus assembly and entry.
基金Inserm, France Université Louis Pasteur, France+3 种基金the European Union (Virgil Network of Excellence)the DeutscheForschungsgemeinschaft (Ba1417/11-1), Germanythe ANRchair of excellence program and ANRS, FranceInserm "PosteVert" research fellowship in the framework of Inserm EuropeanAssociated Laboratory Inserm U748-Department of Medicine Ⅱ,University of Freiburg, Germany
文摘Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodiesfor control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.
基金supported by the National Natural Science Foundation of China (Grant No.31372440)
文摘The surface glycoproteins of coronaviruses play an important role in receptor binding and cell entry. Different coronaviruses interact with their specific receptors to enter host cells. Lentiviruses pseudotyped with their spike proteins(S) were compared to analyze the entry efficiency of various coronaviruses. Our results indicated that S proteins from different coronaviruses displayed varied abilities to mediate pseudotyped virus infection. Furthermore, the cell tropisms of porcine epidemic diarrhea virus(PEDV) and transmissible gastroenteritis virus(TGEV) have been characterized by live and pseudotyped viruses. Both live and pseudoviruses could infected VeroCCL-81(monkey kidney), Huh-7(human liver), and PK-15(pig kidney) cells efficiently. CCL94(cat kidney) cells could be infected efficiently by TGEV but not PEDV. Overall, our study provides new insights into the mechanisms of viral entry and forms a basis for antiviral drug screening.
基金This work is supported in part by grants from the National Natural Science Foundation of China(31672693,31972838 and 31400139,31372565).
文摘Grass carp reovirus(GCRV),the genus Aquareovirus in family Reoviridae,is viewed as the most pathogenic aquareovirus.To understand the molecular mechanism of how aquareovirus initiates productive infection,the roles of endosome and microtubule in cell entry of GCRV are investigated by using quantum dots(QDs)-tracking in combination with biochemical approaches.We found that GCRV infection and viral protein synthesis were significantly inhibited by pretreating host cells with endosome acidification inhibitors NH4Cl,chloroquine and bafilomycin A1(Bafi).Confocal images indicated that GCRV particles could colocalize with Rab5,Rab7 and lysosomes in host cells.Further ultrastructural examination validated that viral particle was found in late endosomes.Moreover,disruption of microtubules with nocodazole clearly blocked GCRV entry,while no inhibitory effects were observed with cytochalasin D treated cells in viral infection,hinting that intracellular transportation of endocytic uptake in GCRV infected cells is via microtubules but not actin filament.Notably,viral particles were observed to transport along microtubules by using QD-labeled GCRV.Altogether,our results suggest that GCRV can use endosomes and microtubules to initiate productive infection.
文摘Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. We aimed to review this relation in a concise way. This review article includes a large number of patients from both western and eastern countries with no clear difference of liver affection. The more severe and frequent liver injury, the more severe COVID-19 infection. Up to half of patients developed hepatitis with serum ALT elevation. Both hepatocellular and/or ductular injury were observed as evidenced by alkaline phosphatase elevation. Increase incidence of morbidity and mortality had been recorded in patients with CLD. Cirrhosis mortality extended in line with the Child-Turcotte-Pugh class. The incidence of ACLF in CLD patients with COVID 19 is not clear. There are no significant associations with the etiology of liver disease and death in cirrhosis. COVID-19 hinders HCV elimination by 2030. Patients should continue their medications if already receiving treatment. Patients with occult or resolved HBV and COVID-19 who are receiving immunosuppressive agents should use antiviral therapy to prevent viral flare-ups.
基金SP acknowledges funding by BMBF(01KI2006D,01KI20328A,01KI20396,01KX2021)the Ministry for Science and Culture of Lower Saxony(14-76103-184,MWK HZI COVID-19)+3 种基金the German Research Foundation(DFGPO 716/11-1,PO 716/14-1)MSW received unrestricted funding from Sartorius AG,Lung Research.HMJ received funding from BMBF(01KI2043,NaFoUniMedCovid19-COVIM:01KX2021)Bavarian State Ministry for Science and the Arts and Deutsche Forschungsgemeinschaft(DFG)through the research training groups RTG1660 and TRR130.
文摘Since the beginning of the COVID-19 pandemic,multiple SARS-CoV-2 variants have emerged.While some variants spread only locally,others,referred to as variants of concern,disseminated globally and became drivers of the pandemic.All SARS-CoV-2 variants harbor mutations relative to the virus circulating early in the pandemic,and mutations in the viral spike(S)protein are considered of particular relevance since the S protein mediates host cell entry and constitutes the key target of the neutralizing antibody response.As a consequence,mutations in the S protein may increase SARS-CoV-2 infectivity and enable its evasion of neutralizing antibodies.Furthermore,mutations in the S protein can modulate viral transmissibility and pathogenicity.
基金This work was supported by the national key project for infectious dis-ease control and prevention(Grant no 2018ZX10711-001)the Strate-gic Priority Research Program of Chinese Academy of Sciences(No.XDB29050201).
文摘Ebola virus(EBOV)is one of the most pathogenic viruses in humans which can cause a lethal hemorrhagic fever.Understanding the cellular entry mechanisms of EBOV can promote the development of new therapeutic strategies to control virus replication and spread.It has been known that EBOV virions bind to factors expressed at the host cell surface.Subsequently,the virions are internalized by a macropinocytosis-like process,followed by being trafficked through early and late endosomes.Recent researches indicate that the entry of EBOV into cells requires integrated and functional lipid rafts.Whilst lipid rafts have been hypothesized to play a role in virus entry,there is a current lack of supporting data.One major technical hurdle is the lack of effective approaches for observing viral entry.To provide evidence on the involvement of lipid rafts in the entry process of EBOV,we generated the fluorescently labeled Ebola virus like particles(VLPs),and utilized single-particle tracking(SPT)to visualize the entry of fluorescent Ebola VLPs in live cells and the interaction of Ebola VLPs with lipid rafts.In this study,we demonstrate the compartmentalization of Ebola VLPs in lipid rafts during entry process,and inform the essential function of lipid rafts for the entry of Ebola virus.As such,our study provides evidence to show that the raft integrity is critical for Ebola virus pathogenesis and that lipid rafts can serve as potential targets for the development of novel therapeutic strategies.
