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.
This proposal explores whether it might be possible to safely improve innate immune resistance to bacterial infection by tailoring host responses to cytokines called interferons. These interferons regulate the ability of macrophages and other myeloid cells to kill microbes. Our efforts, if successful, may lead to new therapies for treatment of acute and chronic microbial infections.
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