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

描述(由申请人提供)：A类细胞内致病菌Francisella tularensis、B类单核细胞增生性李斯特菌、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为从刺激宿主产生I型干扰素(干扰素)中受益。我们之前对单核细胞增多性乳杆菌的研究揭示了一种机制，即干扰素可以增加宿主对这些感染的易感性。我们发现，干扰素通过导致髓系细胞II型干扰素受体的表达迅速减少而抑制巨噬细胞的激活。在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进行实验测试，以防止干扰素下调髓系细胞IFNGR的宿主靶向干预在黏膜和全身细菌感染的背景下具有治疗效果。在目标1中，我们将研究我们实验室开发的不下调髓系细胞中IFNGR的转基因小鼠是否增强了对全身和粘膜细菌感染的抵抗力。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暴露前和暴露后的潜在治疗。在R33阶段，我们概述了我们的战略，以筛选更多的IFNGR下调调节的小分子抑制剂。我们还将描述SM抑制剂的作用，并确定它们的宿主靶点。目标3概述了我们的筛选方法和二次筛选，我们将使用这些方法来识别IFNGR下调调节的选择性小分子抑制剂。在目标4中，我们将定义这些抑制剂对组成性和干扰素调节的巨噬细胞基因表达的全球影响，并使用SM抑制剂来识别新的宿主蛋白，这些蛋白有助于干扰素下调IFNGR，从而可能成为宿主导向干预治疗传染病的靶点。 公共卫生相关性：当适当激活时，巨噬细胞和其他髓系细胞可以有效地吞噬和杀灭细菌。然而，抑制这种激活的宿主因素会促进更严重的细菌感染。我们的研究将调查针对宿主的干预措施，以防止宿主抑制髓系细胞的激活，从而可能提高对细菌感染的抵抗力。

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. PUBLIC HEALTH RELEVANCE: When appropriately activated, macrophages and other myeloid cells can efficiently engulf and kill bacteria. However, host factors that suppress this activation facilitate more severe bacterial infections. Our studies will investigate host-targeted interventions that prevent host suppression of myeloid cell activation and may thus improve resistance to bacterial infections.