IFNGR Down Regulation as a Host Target for Therapy of Infectious Diseases

项目总结： A类细胞内细菌图拉氏方济氏菌、B类细菌李斯特菌 单核细胞增多症、结核分枝杆菌和许多其他重要的人类细胞内病原体 已进化为从刺激宿主产生I型干扰素(干扰素αβ)中受益。我们之前对L. 单核细胞增多症揭示了干扰素αβ增加宿主对这些感染的易感性的机制。 我们发现干扰素αβ通过引起髓系细胞的快速减少来抑制巨噬细胞的激活。 II型干扰素受体γ的表达。在此R21/R33提案的R21阶段，我们将使用新颖的 我们实验室开发的试剂和工具用于实验测试针对宿主的干预措施是否会阻止 干扰素αβ下调髓系细胞干扰素受体在黏膜和骨髓瘤中的治疗作用 全身性细菌感染。在目标1中，我们将调查我们实验室培育的转基因小鼠 不下调髓系细胞中IFNGR的药物增加了对全身和粘膜细菌的耐药性 感染。在目标2中，我们使用在IFNGR下调中起作用的宿主激酶的抑制剂来测试 潜在的暴露前和暴露后治疗。在R33阶段，我们概述了我们的战略，以筛选其他 IFNGR下调的小分子抑制剂。我们还将描述SM抑制剂的作用 并确定它们的宿主目标。目标3概述了我们的筛选方法和我们将用于 鉴定IFNGR下调的选择性小分子抑制剂。在目标4中，我们将定义全局影响 这些抑制剂对构成和干扰素αβ调节巨噬细胞基因表达的影响，并使用SM抑制剂 确定新的宿主蛋白，这些蛋白有助于干扰素αβ下调IFNGR，从而可能成为 以宿主为导向的干预措施，以治疗传染病。

Project Summary: The category A intracellular bacterial pathogen Francisella tularensis, the category B bacterium Listeria monocytogenes, Mycobacterium tuberculosis, and numerous other important human intracellular pathogens have evolved to benefit from stimulating the host to produce type I interferons (IFNαβ). Our prior studies with L. monocytogenes revealed a mechanism by which IFNαβ can increase host susceptibility to these infections. We found that IFNαβ suppresses the activation of macrophages by causing rapid reductions in myeloid cell expression of the receptor for type II IFN, IFNγ. In the R21 phase of this R21/R33 proposal, we will use novel reagents and tools developed in our lab to experimentally test whether host-targeted interventions that prevent down regulation of myeloid cell IFNGR by IFNαβ have therapeutic effects in the context of mucosal and systemic bacterial infections. In Aim 1, we will investigate whether transgenic mice developed in our laboratory that do not down regulate IFNGR in myeloid cells have increased resistance to systemic and mucosal bacterial infection. In Aim 2, we use inhibitors of a host kinase that plays a role in IFNGR down regulation to test for potential pre- and post-exposure therapy. In the R33 phase, we outline our strategy to screen for additional small molecule inhibitors of IFNGR down regulation. We will also characterize the effects of the SM inhibitors and identify their host targets. Aim 3 outlines our screening approach and secondary screens we will use to identify selective small molecule inhibitors of IFNGR down regulation. In Aim 4, we will define the global effects of these inhibitors on constitutive and IFNαβ-regulated macrophage gene expression and use SM inhibitors to identify novel host proteins that contribute to IFNGR down regulation by IFNαβ and thus may be targets for host-directed interventions to treat infectious diseases.