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

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Project Summary: Macrophages and other myeloid cells 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 - and in some cases opposing - effects on myeloid cell function. IFN? activates microbicidal activity of macrophages and typically reduces host susceptibility to intracellular microbes. Conversely, IFN?? suppresses myeloid cell activation by IFN? and increases host susceptibility to certain bacteria. The mechanisms by which IFN?? suppresses myeloid cell activation remain incompletely understood. Our prior studies showed that IFN?? triggers down regulation of the receptor for IFN?, IFNGR1, specifically in myeloid cells. This down regulation occurs at the transcriptional level and is independent of STAT proteins important for other, canonical, responses to type I IFNs. We have begun to investigate the mechanisms for ifngr1 down regulation and have identified inhibitors of this process and obtained evidence that two specific host proteins not previously associated with type I IFN responses are important for IFNGR down regulation. In this exploratory R21 grant application we propose experiments to further dissect how these proteins intersect the type I IFN signaling pathway in macrophages and to evaluate their impact on global myeloid cell gene expression patterns in resting and IFN?-stimulated states. Information from these studies will provide insight into immune-suppressive non-canonical responses to IFN?? and their effects on host susceptibility to microbial infections.
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