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

描述（由申请人提供）：巨噬细胞和其他骨髓细胞类型是感染先天免疫反应的关键参与者。髓细胞的发育、募集、激活和杀微生物活性是由I型和II型干扰素（IFN和IFN）调控的。IFN和IFN？在微生物感染过程中同时产生，但对髓细胞有不同的影响。干扰素吗?激活巨噬细胞杀微生物活性，通常降低宿主对细胞内微生物的敏感性。相反，IFN抑制髓细胞活化，增加宿主对某些细胞内细菌的易感性。IFN加剧细菌感染的机制仍然知之甚少。在这个探索性的R21资助申请中，我们测试了IFN由于其抑制骨髓细胞免疫的能力而增加对细菌感染的易感性的假设。在第一个目的中，我们确定IFN下调髓细胞IFNGR表达是否会损害髓细胞活化并增加宿主对感染的易感性。在第二个目标中，我们测试了抑制ifngr1基因表达的新型非规范IFN反应途径是否也会损害其他对骨髓细胞活化重要的基因的表达，以及抑制该途径是否会增加宿主对感染的抗性。来自这些研究的信息将提供深入了解对IFN的非规范反应增加宿主对微生物感染易感性的机制。

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.