MYCOBACTERIUM TUBERCULOSIS;INDUCED MACROPHAGE SIGNALLING

描述(改编自申请人的摘要)：结核病(TB)是 世界上最常见的致命传染病，仍然是对 美国的健康状况。虽然改进了病例查找和访问 治疗降低了美国的结核病发病率，进一步 结核病控制和治疗的改进取决于更好地了解 结核病的发病机制。巨噬细胞对于防御感染是必不可少的， 它们是结核病发病机制的核心。当巨噬细胞遇到最多 细菌，它们吞噬并杀死它们。相比之下，巨噬细胞吞噬， 但不要杀死结核分枝杆菌，即使他们受到干扰素-伽马的刺激。 最近在圆周率实验室的实验表明，其中一个意味着M。 结核病用来逃避巨噬细胞的杀伤是为了阻断信号 干扰素-γ启动的转导通路。私家侦探发现 结核分枝杆菌感染巨噬细胞可阻断多个巨噬细胞 对干扰素-γ的反应，并发现这种信号的干扰 在远端减少干扰素-γ反应基因的转录激活 步入信号通路。巨噬细胞感染结核分枝杆菌引起 释放一种或多种抑制干扰素-γ信号的可溶性因子 未感染的巨噬细胞。转化生长因子-β、IL-4、IL-6、IL-10和前列腺素E_2 无法解释这一现象。PI建议确定组件 结核分枝杆菌引起干扰素-γ信号的抑制。一 有待检验的假设是结核分枝杆菌感染巨噬细胞 诱导抑制物结合特定DNA元件在启动子区域 干扰素伽马反应基因。最后，PI将提纯可溶的 条件培养液中存在的抑制受感染细胞的因子 未感染巨噬细胞中的干扰素-伽马信号。拟议中的实验 将增进对结核病发病机制的认识，并将 提供必要的洞察力以制定有效的方法来增强 对结核分枝杆菌的保护性免疫反应。

DESCRIPTION(Adapted from the applicant's abstract): Tuberculosis (TB) is the most common fatal infectious disease in the world, and remains a threat to health in the United States. While improved case finding and access to treatment have reduced the incidence of TB in the United States, further improvements in TB control and therapy depend on better understanding of the pathogenesis of TB. Macrophages are essential for defense against infections, and are central to the pathogenesis of TB. When macrophages encounter most bacteria, they phagocytose and kill them. In contrast, macrophages phagocytose, but do not kill M. tuberculosis, even when they are stimulated with IFN gamma. Recent experiments in the PI's laboratory reveal that one means that M. tuberculosis uses to evade killing by macrophages is to block the signal transduction pathway initiated by interferon gamma. The PI has found that infection of macrophages with M. tuberculosis blocks several macrophage responses to IFN gamma, and has found that this disruption of signalling reduces transcriptional activation of IFN gamma-responsive genes at a distal step in the signalling pathway. M. tuberculosis infection of macrophages causes release of one or more soluble factors that inhibit IFN gamma signaling in uninfected macrophages. TGF-beta, IL-4, IL-6, IL-10, and prostaglandin E2 cannot account for this phenomenon. The PI proposes to identify the component of M. tuberculosis that initiates the inhibition of IFN gamma signaling. One hypothesis to be tested is that infection of macrophages by M. tuberculosis induces a repressor that binds specific DNA elements in the promoter region of interferon gamma-responsive genes. Finally, the PI will purify the soluble factor present in the conditioned medium from infected cells that inhibits interferon gamma signaling in uninfected macrophages. The proposed experiments will enhance the understanding of the pathogenesis of tuberculosis, and will provide insight essential for developing effective approaches to enhancing the protective immune response to M. tuberculosis.