Modulation of innate immunity by microbial factors

描述（由申请人提供）：摘要：本提案审查了 微生物和宿主来源的活化因子对细胞增殖的调节作用 先天免疫系统在人类疾病的实验模型。 人类睡眠病是一种致命的疾病，其特征是广泛的 淋巴组织的功能、组织学和病理学变化 锥虫属感染的宿主在这些变化中， 单核吞噬细胞系统细胞的数量和活化状态。 感染时巨噬细胞的激活是对释放的分子的反应 以及由T细胞响应寄生虫产生的IFN-γ 抗原这些激活事件在整个感染过程中间歇性发生， 与寄生虫生长和免疫破坏波相关;因此 锥虫感染代表了一种自然模型， 先天免疫系统的组成部分以反复的方式暴露于 微生物因素（“危险”信号）和宿主细胞因子。我们目前的证据 这两个因素在巨噬细胞活化过程中产生不同的模式， 感染，以及不同激活的平衡或相互作用 信号可以决定疾病的进展和感染的结果。 由于巨噬细胞活化反应是基于不同的 膜相关的信号事件，因为巨噬细胞活化是 与宿主保护密切相关，这是一项了解 巨噬细胞激活的基础显然是一个重要的科学步骤， 理解宿主-寄生虫关系和巨噬细胞的概念 微生物感染期间的共激活。因此，本提案审查了 细胞生物学和分子信号的基本要素， 非洲锥虫巨噬细胞活化反应。最终目标是 揭示与巨噬细胞活化相关的新的调节机制 可以用来增强对疾病的抵抗力。

DESCRIPTION (provided by applicant): Summary: This proposal examines the regulatory effects of microbe- and host-derived activation factors on the innate immune system in an experimental model of human disease. Human Sleeping Sickness is a fatal disease characterized by extensive functional, histological and pathological changes in the lymphoid tissues of Trypanosoma spp. infected hosts. Among these changes is an increase in the numbers and activation state of cells of the mononuclear phagocyte system. Macrophage activation during infection occurs in response to molecules released by the parasite as well as to IFN-y produced by T cells in response to parasite antigens. These activation events occur episodically throughout infection, associated with waves of parasite growth and immune destruction; thus trypanosome infections represent a natural model in which the macrophage component of the innate immune system is exposed in a recurrent manner to microbial factors ("danger" signals) and to host cytokines. We present evidence that the two factors produce distinct patterns of macrophage activation during infection, and that the balance or interaction of the different activation signals may determine the progression of disease and outcome of infection. Since the macrophage activation response is based on distinct membrane-associated signaling events, and since macrophage activation is intimately linked to host protection, an effort to understand the molecular basis for macrophage activation is clearly an important scientific step towards understanding the host-parasite relationship and the concept of macrophage co-activation during microbial infection. Therefore, this proposal examines basic elements of cell biology and molecular signaling to dissect the macrophage activation response in African trypanosomiasis. The ultimate goal is to uncover novel regulatory mechanisms associated with macrophage activation that can be exploited to provide greater resistance to disease.