Interferon gamma-dependent immunity to Mycobacterium tuberculosis mediated by regulation of inflammation by lung macrophages - PROJECT SUMMARY / ABSTRACT Tuberculosis (TB) is an ancient disease that continues to be a leading cause of infectious morbidity and mortality, with approximately 1.5 million deaths per year. Efforts toward development of effective TB vaccines and host-directed therapies have been hampered by an insufficient understanding of immunity to Mycobacterium tuberculosis (Mtb). For decades, the central mechanism by which the immune system has been understood to control Mtb is through activation of direct Mtb-restricting mechanisms in infected lung monocyte-derived macrophages (MDMs) by the cytokine interferon gamma (IFNγ). However, data from humans and animal models has often been challenging to reconcile with this model. Meanwhile, increasing attention has been paid to the role of the lung inflammatory environment, cellular milieu, and immunometabolism in controlling Mtb and preventing TB disease. Here, we propose and test the novel hypothesis that IFNγ-activated MDMs regulate immunity to Mtb largely by modulating the cellular and inflammatory state of the lung, thereby limiting immunopathology and promoting phagocyte bacterial restriction in trans. Furthermore, we posit that the enzyme aconitate decarboxylase 1 (ACOD1, also known as immune-responsive gene 1 (IRG1)) is a primary mediator of this host-protective activity. The rationale supporting this proposal includes 1) our observations that absence of T cell-derived IFNγ leads to a profound susceptibility to Mtb burden and disease pathology associated with inflammation, type 2 cytokines, granulocyte infiltration to TB lesions, and inhibition of Irg1; 2) our re-analysis of published flow cytometry data revealing results supporting a cell-extrinsic mechanism of Mtb restriction by IFNγ-activated MDMs, 3) published evidence that myeloid cell expression of Irg1 is protective against Mtb in trans, 4) mounting evidence to support a critical role for IRG1 and its enzymatic product, itaconate, in suppressing inflammation, alternative macrophage activation, and granulocyte responses. In Aim 1, we will assess the link between IFNγ and IRG1-mediated immunity to Mtb, using bone marrow chimeric mice and itaconate administration to determine whether and how deficiency in Irg1 phenocopies Ifngr deficiency in terms of effects on cell-intrinsic and extrinsic MDM immune mechanisms in TB. In Aim 2, we determine the relative contribution of neutrophils vs eosinophils to TB lesion and disease severity in mice deficient in either IFNγ or IRG1. The proposal is innovative because it investigates an unexpected mode of action for IFNγ-activated MDMs in Mtb, as well as a potential pathogenic role for eosinophils in Mtb, which has not previously been documented. The Research Strategy and Career Development Plans described here will support Dr. Maciag to launch her independent research career as a physician-scientist investigating immunity to TB.
