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Innate Immunity Hemorrhagic fever viruses

先天免疫出血热病毒

基本信息

批准号：
8233435
负责人：
Robert William Finberg
金额：
$ 46.31万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233435
关键词：
Affect Agonist Arenavirus CD14 gene Cells Cessation of life Containment Cytoplasmic Receptors Development Disease Doctor of Medicine Ebola virus Filovirus Frankfurt-Marburg Syndrome Virus Gene Expression Generations Genes Host Defense Human IRF1 gene Immune Immune response Immune system Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Response Pathway Interferon Type I Interferons Knockout Mice Lead Lymphocytic choriomeningitis virus Mammals Mediating Molecular Morbidity - disease rate Mus Natural Immunity New England Pathogenesis Pathway Analysis Pathway interactions Pattern Pharmaceutical Preparations Plasmids Preclinical Drug Evaluation Production Proteins RNA Helicase RNA Sequences Regulation Research Project Grants Role Satellite Viruses Screening procedure Series Signs and Symptoms Specificity Structure TLR2 gene TLR6 gene Therapeutic Toll-like receptors Viral Viral Genes Viral Hemorrhagic Fevers Virus Virus Diseases acquired immunity analog base biodefense cell type cytokine drug production hemorrhagic fever virus in vivo mortality mouse model novel strategies novel vaccines pathogen prevent receptor research study response small molecule time use viral RNA

项目摘要

NERCE Project 17: Innate immunity hemorrhagic fever viruses, Robert W. Finberg, M.D., UMass The innate immune response to hemorrhagic fever viruses determines the early morbidity and mortality associated with these illnesses. This is a consequence of both induction of host inflammatory cytokines by the virus, as well as the initial host defense against the virus which includes the production of type 1 interferons (IFN) that prevent viruses from replicating. Our initial series of experiments defined the Toll Like Receptor (TLR) responses to hemorrhagic fever viruses, focusing on Lymphocytic Choriomeningitis Virus (LCMV) as a prototypic arenavirus. By using human cells transfected with CD14 and TLR2 and knockout mice, we were able to demonstrate that the LCMV specific inflammatory cytokine response is mediated through TLR2, TLR6, and CD14. Screening for small molecules that inhibited LCMV-mediated activation of NFkB, defined a subset of compounds that may be suitable for preventing TLR2 mediated viral disease by blocking the induction of inflammatory cytokines ("cytokine storm") associated with many lethal viral infections. Our studies of the responses of mouse and human cells to the arenavirus LCMV, and two filoviruses that cause hemorrhagic fever, namely Ebola and Marburg, reveal that these viruses cause a rapid induction of inflammatory cytokines in host cells. We plan to use the compounds we have identified as a result of our screen, in human cells and in mouse models challenged with different hemorrhagic fever to define the mechanisms of action of these small molecules and determine if they can prevent the "cytokine storm". Initial virus containment in mammals is dependent upon the induction of type 1 IFN, which is commonly mediated through cytoplasmic RNA helicases termed RIG-l-like receptors. In this project we will define the genes and pathways involved in the induction of IFN by hemorrhagic fever viruses and search for small molecules that might augment that response. In addition we will investigate host genes directly or indirectly modulated by infection with these viruses and the effects of the small molecules obtained through our screens on expression of these genes

NERCE项目17：先天免疫性出血热病毒，罗伯特W。芬伯格，医学博士，麻省大学对出血热病毒的天然免疫应答决定了早期发病率和死亡率与这些疾病有关。这是由炎症因子诱导宿主炎性细胞因子引起的结果。病毒，以及针对病毒的初始宿主防御，包括1型的产生，干扰素（IFN），阻止病毒复制。我们最初的一系列实验定义了Toll Like 淋巴细胞脉络丛脑膜炎病毒对出血热病毒的TLR反应（LCMV）作为原型沙粒病毒。通过使用用CD 14和TLR 2转染并敲除的人细胞，在小鼠中，我们能够证明LCMV特异性炎症细胞因子应答是由 TLR 2、TLR 6和CD 14。筛选抑制LCMV介导的活化的小分子， NFkB定义了可适用于通过以下方式预防TLR 2介导的病毒性疾病的化合物的子集：阻断与许多致死性病毒相关的炎性细胞因子（“细胞因子风暴”）的诱导，感染. 我们研究了小鼠和人类细胞对沙粒病毒LCMV和两种丝状病毒的反应，引起出血热，即埃博拉病毒和马尔堡，揭示这些病毒引起快速诱导宿主细胞中的炎性细胞因子。我们计划使用我们已经确定的化合物作为我们的结果，筛选，在人类细胞和小鼠模型中挑战不同的出血热，以确定这些小分子的作用机制，并确定它们是否可以防止“细胞因子风暴”。初始哺乳动物中的病毒遏制依赖于1型IFN的诱导，通过称为RIG-1样受体的细胞质RNA解旋酶。在这个项目中，我们将定义基因，参与出血热病毒诱导IFN的途径，并寻找可能会增加这种反应。此外，我们还将研究直接或间接受这些病毒的感染以及通过我们的筛选获得的小分子对这些基因的表达