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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：
7669766
负责人：
Robert William Finberg
金额：
$ 43.74万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-25 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7669766
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：先天免疫出血热病毒，Robert W. Finberg，医学博士，麻省大学对出血热病毒的先天免疫反应决定了早期发病率和死亡率与这些疾病有关。这是宿主炎症细胞因子诱导的结果病毒，以及宿主对病毒的初始防御，包括 1 型病毒的产生干扰素 (IFN) 可防止病毒复制。我们最初的一系列实验定义了 Toll Like 受体（TLR）对出血热病毒的反应，重点关注淋巴细胞脉络膜脑膜炎病毒（LCMV）作为原型沙粒病毒。使用转染 CD14 和 TLR2 并敲除的人类细胞在小鼠中，我们能够证明 LCMV 特异性炎症细胞因子反应是介导的通过 TLR2、TLR6 和 CD14。筛选抑制 LCMV 介导的激活的小分子 NFkB 定义了可能适合预防 TLR2 介导的病毒性疾病的化合物子集阻断与许多致命病毒相关的炎症细胞因子（“细胞因子风暴”）的诱导感染。我们对小鼠和人类细胞对沙粒病毒 LCMV 和两种丝状病毒反应的研究引起出血热，即埃博拉病毒和马尔堡病毒，表明这些病毒会导致快速诱导宿主细胞中的炎症细胞因子。我们计划使用我们已经确定的化合物在人类细胞和遭受不同出血热挑战的小鼠模型中进行筛选，以确定这些小分子的作用机制，并确定它们是否可以预防“细胞因子风暴”。最初的哺乳动物体内的病毒遏制取决于 1 型干扰素的诱导，这通常是介导的通过称为 RIG-1 样受体的细胞质 RNA 解旋酶。在这个项目中，我们将定义基因和出血热病毒诱导干扰素的途径并寻找小分子可能会增强这种反应。此外，我们将研究直接或间接调节的宿主基因这些病毒的感染以及通过我们的筛选获得的小分子的影响这些基因的表达