Innate Immunity & Hemorrhagic Fever Viruses

这个项目将研究先天免疫系统在病毒病理生理学中的作用。 出血热。将研究两种可能导致生物恐怖主义的病毒：1)埃博拉病毒，一种 丝状病毒，引起以发烧、白细胞减少、休克和死亡为特征的急性疾病，以及2) 淋巴细胞性脉络膜脑膜炎病毒LCMV是一种引起疾病的病毒，其特征是 小鼠的白细胞减少和血小板减少，以及人类的脑膜炎。与高死亡率相关的 埃博拉病毒感染已被证明与病毒感染后细胞因子的释放直接相关 巨噬细胞感染。埃博拉病毒诱导这种细胞因子反应的机制将被定义 将对化合物进行筛选，以确定其抑制这一活性的能力。初步数据显示， Toll样受体2(TLR-2)和CD14在LCMV细胞因子应答中的作用。TLR-2和CD14是模式 识别蛋白在细菌败血症中的作用最近已经被确定。这两者也被联系在一起 对病毒的免疫反应。利用转基因细胞系和可用的基因敲除小鼠 这些蛋白质影响细胞因子的初始诱导以及随后的 将定义对LCMV和埃博拉病毒的免疫反应。特定的TLR(和其他“模式” 识别蛋白“)参与这些反应以及它们之间的相互作用。 这些对长期带状T细胞免疫的早期识别事件将被调查。这些研究将 从而更好地理解先天免疫系统在调节 出血热病毒的病理生理学，并应导致新的治疗方法 疾病。

This project will examine the role of the innate immune system in the pathophysiology of the viral hemorrhagic fevers. Two viruses which are potential agents of bioterrorism, will be studied: 1) Ebola virus, a filovirus, which induces an acute illness characterized by fever, leucopenia, shock, and death, and 2) Lymphocytic Choriomeningitis Virus LCMV an arenavirus which causes an illness characterized by leucopenia and thrombocytopenia in mice and meningitis in humans. The high mortality rate associated with Ebola infection has-been demonstrated to be directly associated with cytokine release which occurs after viral infection of macrophages. The mechanism by which Ebola induces this cytokine response will be defined and compounds will be screened for their ability to inhibit this activity. Preliminary data indicate a major role for Toll Like Receptor 2 (TLR-2) and CD14 in the cytokine response to LCMV. TLR-2 and CD14 are pattern recognition proteins whose role in bacterial sepsis has been recently defined. Both have also been associated with the immune responses to viruses. Using transfected cell lines and available knockout mice the mechanism by which these proteins affect both initial induction of cytokines as well as the subsequent immune responses to LCMV and Ebola virus will be defined. The specific TLRs (and other "pattern recognition proteins") involved in these responses as well as their interactions will be studied. The effect of these early recognition events on long-term Band T cell immunity will be investigated. These studies will result in a better understanding of the role that the innate immune system has in mediating the pathophysiology of hemorrhagic fever viruses and should lead to new therapeutic approaches to these diseases.