Innate Immunity and LCMV

出血热病毒是生物恐怖主义的潜在病原体，因为它们能够在感染后引起发热、出血和死亡。已发现这些症状的发展与炎性细胞因子（包括IL-6、IL-8和TNF-α）的释放有关。在已经充分研究的大多数系统中，炎性细胞因子的释放由模式识别蛋白如CD 14和Toll样受体蛋白（如TLR 2、TLR 3和TLR 4）控制。淋巴细胞脉络丛脑膜炎病毒（LCMV），一种在人类和小鼠中引起疾病的沙粒病毒，是研究出血热病毒发病机制的模型。使用人和小鼠细胞对LCMV的初步研究表明，由LCMV引发的细胞因子的释放受CD 14和TLR 2控制。Toll样受体，因为它们 释放炎性细胞因子的能力在对病原体的应答中具有双重作用。虽然细胞因子的急性释放可能引起可能对宿主有害的症状（发热、休克和出血），但这些相同的细胞因子在启动长期免疫中可能是重要的。为了研究CD 14和TLR的作用，将使用转染的人细胞以及TLR敲除小鼠和源自TLR敲除小鼠的细胞系。将定义参与产生免疫应答的特定蛋白质，并分离不诱导炎性细胞因子应答的变异病毒，并表征其在添加或不添加佐剂的情况下诱导持久免疫的能力。TLR在NK细胞、B细胞、T细胞和抗原呈递细胞介导的对LCMV的免疫发展中的作用将被进一步研究。 研究了这些研究将有助于了解生物恐怖分子的发病机制，以及如何治疗和预防沙粒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.