Dissecting Dengue Virus Permissiveness using a Stem Cell Differentiation System

使用干细胞分化系统剖析登革热病毒的容许度

• 批准号: 8952031
• 负责人: HENGLI TANG
• 金额: $ 18.39万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952031
• 关键词: Antiviral Agents; Antiviral Therapy; Bite; Cell Communication; Cell Surface Proteins; Cells; Culicidae; Dengue; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Down-Regulation; Drug Targeting; Endoderm; Genes; Goals; Health; Hematopoietic; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; In Vitro; Integration Host Factors; Interferons; Intervention; Knowledge; Liver; Mesoderm; Organ; Pathway interactions; Patients; Pluripotent Stem Cells; Predisposition; Proteins; Public Health; Publishing; RNA Interference; RNA Viruses; Research; Resistance; Role; Specific qualifier value; System; Testing; Therapeutic Intervention; Up-Regulation; Vaccines; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; West Nile virus; Work; Yellow fever virus; anti-hepatitis C; base; cell type; cofactor; env Gene Products; insight; monocyte; new therapeutic target; pathogen; permissiveness; prevent; programs; prophylactic; public health relevance; research study; stem cell differentiation; transcriptome sequencing; virus envelope; virus host interaction; virus tropism

 DESCRIPTION (provided by applicant): The broad, long-term goal of our research program is to advance knowledge of virus-host cell interactions by characterizing cellular cofactors essential for viral infections, particularly positive- strand RNA viruses such as dengue virus (DENV) and hepatitis C virus (HCV). The current proposal focuses on DENV, which infects millions of people worldwide and poses major emerging threat to human health. Understanding how DENV interacts with the host cell is of critical importance to the development of antiviral drugs and a prophylactic vaccine, both of which are currently lacking. Building upon our previous work on in vitro hepatic differentiation and HCV infection which led to the identification of host determinants of HCV susceptibility, we propose to investigate the cellular parameters that contribute to DENV permissiveness in both monocytes and hepatic cells. We have uncovered a discrete cellular transition to DENV permissiveness during directed differentiation of pluripotent stem cells in preliminary experiments. We will scrutinize the gene profiles during this transition period to identify putative host factors required for DENV infection which in turn may be exploited as new drug targets for antiviral therapy. In addition, we will analyze the contribution of downregulated antiviral proteins to the transition to DENV susceptibility and investigate the mechanism of action for any antiviral proteins that are effective at suppressing DENV infection. The results of the proposed studies will not only provide significant insights into how DENV hijacks cellular proteins and machineries to facilitate its own replication in human cells; but also may reveal new therapeutic targets for antiviral intervention directed at important human pathogens.

 描述（由适用提供）：我们的研究计划的广泛长期目标是通过表征对病毒感染所必需的细胞辅助因子，尤其是阳性RNA病毒（例如登革热病毒（DENV）和丙型肝炎病毒（HCV）所必需的细胞辅助因子（尤其是阳性的RNA病毒），可以提高对病毒宿主宿主相互作用的知识。当前的提案着重于DENV，DENV感染了全球数百万的人，并对人类健康构成了重大的威胁。了解DENV与宿主细胞的相互作用对于抗病毒药物的开发和预防性疫苗至关重要，目前缺乏两种预防性疫苗。基于我们以前关于体外肝炎分化和HCV感染的工作，这导致了鉴定 我们将在此过渡期审查基因谱，以确定DENV感染所需的推定宿主因素，而DENV感染可能被用作抗病毒药疗法的新药物靶标。此外，我们将分析下调的抗病毒蛋白对DENV易感性的过渡的贡献，并研究有效抑制DENV感染的任何抗病毒蛋白的作用机理。拟议研究的结果不仅将为您提供重大见解 DENV如何劫持细胞蛋白和机器以促进其在人类细胞中的复制；但也可能揭示了针对重要的抗病毒干预措施的新的治疗靶标 人类病原体。