Pharmacologic Inhibition of Macrophage Triglyceride Biosynthesis Pathways Does Not Improve Mycobacterium tuberculosis Control in Infected Mice.

Abstract

Tuberculosis necrotic granulomas contain triglyceride-rich macrophages (foam cells) with reduced antimicrobial functions. We assessed the ability of 2 compounds to reduce the triglyceride content and Mycobacterium tuberculosis (Mtb) burden in infected human monocyte-derived macrophages and in the lungs of Mtb-infected C3HeB/FeJ mice: A-922500 (DGATi), an inhibitor of diacylglycerol O-acyltransferase 1, and LY2584702 (p70S6Ki), an inhibitor of p70 S6 kinase. DGATi and p70S6Ki significantly reduced the lipid content and bacillary burden in Mtb-infected macrophages. Each inhibitor reduced the cellular triglyceride content in bronchoalveolar lavage samples of Mtb-infected mice. After 6 weeks of treatment, p70S6Ki alone reduced the lung bacterial burden in Mtb-infected mice. However, DGATi alone and DGATi or p70S6Ki in combination with isoniazid did not reduce lung bacterial burden or alter lung inflammation. These findings provide further insight into the role of foam cells in tuberculosis pathogenesis and the utility of interventions targeting these cell populations as adjunctive host-directed therapies.