Non-canonical responses to IFNab in the suppression of macrophage immunity

描述(由申请人提供)：巨噬细胞和其他类型的髓系细胞是对感染的先天免疫反应的关键参与者。髓系细胞的发育、募集、激活和杀菌活性受I型和II型干扰素(干扰素和干扰素)的调节。干扰素和干扰素？在微生物感染期间同时产生，但对髓系细胞有不同的影响。干扰素？激活巨噬细胞杀菌活性，通常降低宿主对细胞内微生物的敏感性。相反，干扰素抑制髓系细胞的激活，增加宿主对某些细胞内细菌的敏感性。干扰素加剧细菌感染的机制仍然知之甚少。在这个探索性的R21授权应用中，我们测试了这样一个假设，即干扰素由于其抑制髓系细胞免疫的能力而增加了对细菌感染的易感性。在第一个目标中，我们确定干扰素下调髓系细胞IFNGR的表达是否会损害髓系细胞的激活并增加宿主对感染的易感性。在第二个目的中，我们测试了抑制ifngr1基因表达的新的非规范干扰素反应途径是否也损害了对髓系细胞激活至关重要的其他基因的表达，以及抑制这一途径是否增加了宿主对感染的抵抗力。来自这些研究的信息将深入了解对干扰素的非规范反应增加宿主对微生物感染的易感性的机制。

DESCRIPTION (provided by applicant): Macrophages and other myeloid cell types are key players in the innate immune response to infection. Myeloid cell development, recruitment, activation, and microbicidal activity are regulated by type I and II interferons (IFN¿¿ and IFN?). IFN¿¿ and IFN? are concurrently produced during microbial infections but have different effects on myeloid cells. IFN? activates macrophage microbicidal activity and typically reduces host susceptibility to intracellular microbes. Conversely, IFN¿¿ suppresses myeloid cell activation and increases host susceptibility to certain intracellular bacteria. The mechanisms by which IFN¿¿ exacerbates bacterial infections remain poorly understood. In this exploratory R21 grant application we test the hypothesis that IFN¿¿ increases susceptibility to bacterial infections due to its ability to suppress myeloid cell immunity. In the first Aim, we determine whether down regulation of myeloid cell IFNGR expression by IFN¿¿ impairs myeloid cell activation and increases host susceptibility to infection. In the second Aim, we test whether the novel non- canonical IFN¿¿ response pathway that suppresses ifngr1 gene expression also impairs expression of other genes important for myeloid cell activation and whether inhibiting this pathway increases host resistance to infection. Information from these studies will provide insight into the mechanisms by which non-canonical responses to IFN¿¿ increase host susceptibility to microbial infections.