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

描述（由申请人提供）：A类细胞内细菌病原体土拉弗朗西斯菌，B类细菌单核细胞增生李斯特菌，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可以通过刺激宿主产生I型干扰素（IFN）而受益。我们之前对单核增生乳杆菌的研究揭示了IFN可以增加宿主对这些感染的易感性的机制。我们发现IFN通过引起II型IFN受体的骨髓细胞表达的快速降低来抑制巨噬细胞的激活。在这个R21/R33提案的R21阶段，我们将使用我们实验室开发的新试剂和工具来实验测试宿主靶向干预是否在粘膜和全身细菌感染的背景下具有治疗作用，以防止IFN下调髓细胞IFNGR。在Aim 1中，我们将研究在我们实验室培育的不下调骨髓细胞IFNGR的转基因小鼠是否增加了对全身和粘膜细菌感染的抵抗力。在Aim 2中，我们使用在IFNGR下调中起作用的宿主激酶抑制剂来测试潜在的暴露前和暴露后治疗。在R33期，我们概述了筛选IFNGR下调的其他小分子抑制剂的策略。我们还将描述SM抑制剂的作用并确定其宿主靶点。目标3概述了我们的筛选方法和二级筛选，我们将用于识别IFNGR下调的选择性小分子抑制剂。在Aim 4中，我们将定义这些抑制剂对组成型和IFN调控的巨噬细胞基因表达的全球影响，并使用SM抑制剂识别有助于IFN下调IFNGR的新型宿主蛋白，从而可能成为宿主定向干预治疗传染病的靶标。

DESCRIPTION (provided by applicant): 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 (IFN¿¿). Our prior studies with L. monocytogenes revealed a mechanism by which IFN¿¿ can increase host susceptibility to these infections. We found that IFN¿¿ suppresses the activation of macrophages by causing rapid reductions in myeloid cell expression of the receptor for type II IFN, IFN?. 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 IFN¿¿ 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 IFN¿¿-regulated macrophage gene expression and use SM inhibitors to identify novel host proteins that contribute to IFNGR down regulation by IFN¿¿ and thus may be targets for host-directed interventions to treat infectious diseases.