The role of Immunoresponsive gene 1 in protection against infection

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PROJECT SUMMARY/ABSTRACT Hospital acquired infections are a major problem in the United States, affecting approximately 2 million patients and causing at least 90,000 deaths ever year. New strategies are needed to combat these infections, especially in light of rising antimicrobial resistance rates among pathogens. Vaccines, one of the most impactful medical technologies in history, are based on adaptive immunological memory responses, which are long lasting and antigen specific. It is now known that cells of the innate immune system also can mount memory responses, but unlike adaptive memory responses, they provide protection against a broad variety of pathogens. This phenomenon is termed innate immune memory or trained immunity and is a potential solution for preventing infections in vulnerable populations. The mechanisms behind innate immune memory are not well understood. Toll-like receptor 4 ligands, including the vaccine adjuvant monophosphoryl lipid A (MPLA), induce innate immune memory in macrophages. MPLA treatment of macrophages causes metabolic reprogramming as well as increases antimicrobial functions in vitro. In vivo, it protects against Gram-positive bacterial, Gram-negative bacterial, and fungal infections. Our preliminary data shows that MPLA treatment induces high expression of Immunoresponsive gene 1 (Irg1), the enzyme which catalyzes production of itaconate, leading to improved bacterial clearance, an effect that is reduced in Irg1 knockout mice. Itaconate is known to alter metabolism through inhibition of succinate dehydrogenase. It is also an antimicrobial metabolite recently discovered to be delivered to bacteria-containing vacuoles. Based on these findings, we hypothesize that Irg1 and itaconate enable the generation of innate immune memory by facilitating macrophage metabolic reprogramming and augmenting lysosome-mediated antimicrobial functions. Aim 1 will determine the role of Irg1 in generation of the memory phenotype in vitro. Irg1 knockout bone marrow-derived macrophages (BMDM) will be studied to determine the contribution of Irg1 to the metabolic and functional changes associated with memory. Treatment with exogenous itaconate will be explored to determine its ability to induce innate immune memory separately from Irg1 activation. Aim 2 will explore the contributions of Irg1 to MPLA-induced protection against infection and disease tolerance in vivo. Knowledge of the mechanism of innate immune memory is critical to its translation to the clinical setting. This project will be undertaken as part of physician-scientist training through the Vanderbilt MSTP.