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，仍然是一个威胁， 美国的健康状况。虽然改善了病例发现和获得 治疗已经降低了美国结核病的发病率， 结核病控制和治疗的改善取决于更好地了解 结核病的发病机制。巨噬细胞对于抵抗感染是必不可少的， 并且是结核病发病机制的核心。当巨噬细胞遇到大多数 细菌会吞噬并杀死它们相反，巨噬细胞吞噬， 但别杀了M结核病，即使它们被IFN γ刺激。 PI实验室最近的实验表明，一个意味着M。 肺结核逃避巨噬细胞杀伤的方法是阻断信号 由干扰素γ启动的转导途径。PI发现， M.结核病阻碍了几种巨噬细胞 对IFN γ的反应，并发现这种信号传导的中断 减少IFN γ应答基因的转录激活， 信号通路中的一步。M.结核病巨噬细胞感染的原因 释放一种或多种抑制IFN γ信号传导的可溶性因子， 未感染的巨噬细胞TGF-β、IL-4、IL-6、IL-10和前列腺素E2 不能解释这种现象。PI建议识别组件 分枝启动IFN γ信号传导抑制的结核病。一 待检验假设是巨噬细胞被M.结核 诱导一个阻遏物，该阻遏物结合启动子区域中的特异性DNA元件， 干扰素γ应答基因。最后，PI将纯化可溶性 存在于受感染细胞的条件培养基中的因子，其抑制 未感染巨噬细胞中的干扰素γ信号传导。拟议的实验 将提高对结核病发病机制的认识， 提供必要的见解，以便制定有效的办法， 保护性免疫反应结核

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.