Project 1 Immunometabolic Determinants of Susceptibility

Project 1: Immunometabolic determinants of host susceptibility (Project Leader: Sassetti). ABSTRACT: Mycobacterium tuberculosis (Mtb) infection in different individuals, or even in different anatomical sites in the same individual, progresses along a variety of trajectories producing a wide spectrum of clinical outcomes – from asymptomatic control to progressive disease. While

many immunological mechanisms necessary for protective immunity have been identified, and are common between humans and small animal models, the basis for the variable expression of these defenses and the consequent diversity in outcome remains unclear. We have identified an immuometabolic axis that controls the ability of the macrophage to integrate proinflammatory

and regulatory signals and influences Mtb infection outcome. In this Project, we will investigate the mechanisms linking mitochondrial function, the unfolded protein response, and the macrophage’s response to Mtb infection in cellular models, in intact animal models, and in multiple human cohorts. The ultimate goals of the project are: (1) to understand the mechanistic

basis for variable immune response to Mtb infection, (2) to identify new and mechanistically- informative immunometabolic markers of disease progression, and (3) to test the efficacy of candidate immunotherapies in promoting protective immunity.