Genome-wide exome sequencing carried out in NIAID and NIDCR led by Dr Steven Holland and Martha Somerman identified IRF8 point mutations among their patients, suffering from non-tuberculosis mycobacteria (NTM) infection or jaw bone-gum diseases, respectively. pPoint mutations identified in these studies are present either in the N-terminal DNA binding domain or the C-terminal regulatory/interacting domain. The results suggested that IRF8 plays a critical role in protection against mycobacterium infection, both M. Tuberculosis and NTM infection as well as the regulation of osteoclast development in the jaw bone. Previously, it has been shown that IRF8 has a major role in controlling M. Tuberculosis infection. However, the role of IRF8 in regulating NTM has not been studied. We infected bone marrow derived macrophages from wild type and IRF8 knockout mice with M. avium complex, a typical NTM strain. We found that the MAC replicates much more efficiently in IRF8 KO macrophages relative to wild type macrophages. While treatment with IFN gamma educed bacterial growth in wild type macrophages, the cytokine did not have a measurable effect on IRF8 KO macrophages. In collaboration with Dr. Katrin Barber-Mayer in NIAID, we tested MAC infection in IRF8 KO mice. Consistent with the data from in vitro macrophages, MAC spread in IRF8 KO mice much more extensively in various organs, including lung, spleen and liver, relative to wild type mice.
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