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

项目摘要： A类细胞内细菌病原体土拉弗朗西斯菌，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 已经进化到受益于刺激宿主产生I型干扰素（IFNαβ）。我们以前的研究与L。 单核细胞增多症揭示了IFNαβ可以增加宿主对这些感染的易感性的机制。 我们发现IFNαβ通过引起骨髓细胞的快速减少来抑制巨噬细胞的活化， II型IFN受体IFNγ的表达。在R21/R33提案的R21阶段，我们将使用新的 在我们的实验室开发的试剂和工具，以实验测试是否主机靶向干预，防止 IFNαβ下调髓系细胞IFNGR在粘膜和 全身性细菌感染。在目标1中，我们将调查是否转基因小鼠在我们的实验室开发 在骨髓细胞中不下调IFNGR的人对全身和粘膜细菌的抵抗力增加， 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，以筛选额外的 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二级筛选， 鉴定IFNGR下调选择性小分子抑制剂。在目标4中，我们将定义全球影响 这些抑制剂对组成型和IFNαβ调节的巨噬细胞基因表达的影响，并使用SM抑制剂， 鉴定有助于IFNαβ下调IFNGR的新宿主蛋白， 针对宿主的干预措施来治疗传染病。

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.