Grant: Project Grant

Tuberculosis (TB) remains a major threat to global health with increasing numbers of new cases reaching >8 millions in 2023, with 1.3 million death. TB is also a significant concern in Canada, with a recent spike in TB cases in Nunavik Inuit people. The parameters of host-pathogen interactions that determine vulnerability to infection remain incompletely understood. We study rare human patients suffering from recurrent TB, and use monogenic mouse models for human candidate genes to characterize host defenses against mycobacteria. We performed exome sequencing on a con-sanguinous family with three affected siblings presenting with recurring pulmonary TB. These studies identified a single homozygous non-sense variant in the human RARRES3 gene in the three patients. RARRES3 encodes a membrane-bound phospholipase A and acetyl transferase expressed in macrophages. In these cells, RARRES3 expression is activated by pro-inflammatory molecules and cytokines which requires IRF1, a gene which inactivation also causes susceptibility to mycobacteria. We will study the mechanisms by which RARRES3 contributes to host anti-mycobacterial defenses. We have created a mouse mutant defective in RARRES3 and will use this mutant to study the causal relationship between loss of RARRES3 and susceptibility to mycobacterial infections in vivo. We will also determine which cell type(s) of the lymphoid and myeloid lineages is responsible for the effects. At the cellular level, we will establish the subcellular localization of RARRES3 including its endomembrane compartments. We will determine whether RARRES3 is present in phagosomes formed in macrophages and contributes to microbicidal activity of phagolysosomes. We will also use global and targeted lipidomics approaches to study the effect of RARRES3 on the lipid composition of myeloid cells and of different membrane compartments derived from them. The proposed studies may uncover novel avenues for therapeutic intervention in tuberculosis.