Sunday, November 24, 2024
11/24/2024
The granuloma is the hallmark pathological structure in tuberculosis (TB). This macrophage-rich complex immune structure can be host-protective but can also be co-opted by mycobacteria for growth and expansion. A critical pathogenic event in TB is granuloma necrosis, which increases bacterial growth, patient morbidity and transmission, thus sustaining the global burden of TB. Using the zebrafish larval model of TB, we have identified multiple genetically-driven host dysregulations that lead to accelerated necrosis of the early granuloma through different innate immune pathways. We identified bacterial virulence determinants that can co-opt these host vulnerabilities to accentuate necrosis. In this proposal, we will investigate three distinct pathways of early granuloma necrosis in the context of innate immunity. Medically induced TNF deficiency is a well-known TB risk factor, and we will investigate how it causes granuloma necrosis. We will investigate our hypothesis that TNF’s dominant effect is as a macrophage pro- survival factor, preventing mycobacterium-beneficial apoptosis. We will study how excess TNF, which we have shown to cause human TB susceptibility, is co-opted by mycobacteria to cause necrosis through a distinct pathway that involves TNF receptor 2. We will pursue our findings that mTOR facilitates a mitochondrial metabolic program that specifically protects against the mitochondrion-damaging effect of the mycobacterial virulence determinant, ESAT-6. We will understand how hypoxia inducible factor 1 (HIF-1), a host resistance factor, becomes pathogenic when expressed constitutively in TB granulomas. Through the lens of mycobacterial pathogenesis, we hope to glean insights into immune signaling, immunometabolism and mitochondrial biology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
