Innate Immunity Hemorrhagic fever viruses

NERCE项目17：先天性免疫出血热病毒，罗伯特·W·芬伯格，医学博士，马萨诸塞州 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。这是由两种途径诱导宿主炎症细胞因子的结果 病毒，以及最初的宿主对病毒的防御，包括产生1型 阻止病毒复制的干扰素(干扰素)。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，重点是淋巴细胞性脉络膜脑膜炎病毒 (LCMV)是一种典型的阿雷诺病毒。利用CD14和TLR2基因及基因敲除的人细胞 小鼠，我们能够证明LCMV特异性炎症细胞因子反应是由 通过TLR2、TLR6和CD14。筛选抑制LCMV介导的细胞因子活化的小分子 NFkB，定义了可能适合于通过以下方式预防TLR2介导的病毒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阿拉伯病毒LCMV和两种丝状病毒的反应 引起出血热，即埃博拉和马尔堡，揭示这些病毒导致快速诱导 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 筛选，在人类细胞和小鼠模型中，用不同的出血热来定义 研究这些小分子的作用机制，并确定它们是否能防止“细胞因子风暴”。首字母 哺乳动物对病毒的控制依赖于1型干扰素的诱导，而1型干扰素通常是由干扰素介导的 通过细胞质RNA解旋酶，称为RIG-L样受体。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和寻找小分子 可能会增强这种反应。此外，我们还将研究直接或间接调节的宿主基因 感染这些病毒以及通过我们的筛查获得的小分子对 这些基因的表达

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