Innate Immunity and LCMV

出血热病毒是潜在的生物恐怖主义因子，因为它们能够在感染后引起发烧、出血和死亡。这些症状的发展已被发现与炎性细胞因子(包括IL-6、IL-8和TNF-α)的释放有关。在大多数已被充分研究的系统中，炎症细胞因子的释放是由模式识别蛋白如CD14和Toll样受体蛋白(如TLR2、TLR3和TLR4)控制的。淋巴细胞性脉络膜脑膜炎病毒(LCMV)是一种在人和小鼠身上均有致病作用的病毒，是研究出血热病毒致病机制的模型。利用人和小鼠细胞对LCMV的初步研究表明，LCMV启动的细胞因子的释放由CD14和TLR2控制。Toll样受体，因为它们的 释放炎性细胞因子的能力在对病原体的反应中具有双重作用。虽然细胞因子的急性释放可能会引起对宿主有害的症状(发烧、休克和出血)，但这些细胞因子在启动长期免疫中可能是重要的。为了研究CD14和TLRs的作用，将使用转基因的人类细胞以及基因敲除小鼠和来自TLR基因敲除小鼠的细胞系。将确定参与产生免疫反应的特定蛋白质，并将分离不诱导炎性细胞因子反应的变异病毒，并对其在添加或不添加佐剂的情况下诱导长期免疫的能力进行表征。TLRs在NK细胞、B细胞、T细胞和抗原提呈细胞介导的LCMV免疫中的作用 学习。这些研究将导致对生物恐怖分子致病机制的深入了解，以及对如何治疗和预防阿拉伯病毒引起的疾病的新见解。

Hemorrhagic fever viruses are potential agents of bioterrorism by virtue of their ability to cause fever, bleeding, and death after infection. The development of these symptoms has been found to be related to the release of inflammatory cytokines (including IL-6, IL-8, and TNF-alpha). In most systems that have been well studied, the release of inflammatory cytokines is controlled by pattern recognition proteins like CD 14 and Toll like receptor proteins (such as TLR2, TLR3, and TLR4). Lymphocytic Choriomeningitis Virus (LCMV), an arenavirus which causes disease in both humans and mice, is a model for studying the pathogenesis of hemorrhagic fever viruses. Preliminary studies of LCMV, using human and mouse cells indicate that the release of cytokines initiated by LCMV is controlled by CD 14 and TLR2. Toll like receptors, because of their ability to release inflammatory cytokines have a dual role in the response to pathogens. While the acute release of cytokines may cause symptoms (fever, shock, and bleeding) that may be detrimental to the host, these same cytokines may be important in initiating long term immunity. To study the role of CD14 and TLRs, transfected human cells as well knockout mice and cell lines derived from TLR knockout mice will be used. The specific proteins involved in the generation of the immune response will be defined and variant viruses that do not induce an inflammatory cytokine response will be isolated and characterized for their ability to induce long lasting immunity with or without the addition of adjuvants. The role of TLRs in the development of immunity to LCMV mediated by NK cells, B, T cells and antigen presenting cells will be studied. These studies will lead to insights about the pathogenesis of bioterrorist agents as well as new insights into how to treat and prevent arenavirus induced disease.