Modulation of innate immunity by microbial factors

描述(由申请人提供)：总结：本建议书审查 微生物和宿主来源的激活因子对细胞周期的调节作用 人类疾病实验模型中的先天免疫系统。 人类睡眠病是一种致命性疾病，其特点是广泛 鸡淋巴组织的功能、组织学和病理变化 锥虫属受感染的宿主。这些变化中有一个是增加了 单核巨噬细胞系统的细胞数量和激活状态。 巨噬细胞在感染过程中被激活是对释放的分子的反应 通过寄生虫以及由T细胞产生的干扰素-γ来应答寄生虫 抗原。这些激活事件在整个感染过程中间歇性地发生， 与寄生虫生长和免疫破坏的浪潮有关；因此 锥虫感染代表了一种自然模式，在这种模式中，巨噬细胞 先天免疫系统的组成部分以循环的方式暴露于 微生物因子(“危险”信号)和宿主细胞因子。我们拿出证据 这两个因素在巨噬细胞激活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 信号可能决定疾病的进展和感染的结果。 因为巨噬细胞的激活反应是基于不同的 膜相关的信号事件，由于巨噬细胞的激活 与宿主保护密切相关，这是为了了解分子 巨噬细胞激活的基础显然是迈向 理解宿主与寄生虫的关系和巨噬细胞的概念 微生物感染过程中的共激活。因此，该提案审查了 细胞生物学和分子信号传递的基本要素 非洲锥虫病患者的巨噬细胞激活反应。最终目标是 揭示与巨噬细胞激活相关的新调节机制 这可以被利用来提供对疾病的更强抵抗力。

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.