Abstract
Lipid metabolism plays a complex and dynamic role in host-pathogen interaction during Mycobacterium tuberculosis infection. While bacterial lipid metabolism is key to the success of the pathogen, the host also offers a lipid rich environment in the form of necrotic caseous granulomas, making this association beneficial for the pathogen. Accumulation of the neutral lipid triglyceride, as lipid droplets within the cellular cuff of necrotic granulomas, is a peculiar feature of pulmonary tuberculosis. The role of triglyceride synthesis in the TB granuloma and its impact on the disease outcome has not been studied in detail. Here, we identified diacylglycerol O-acyltransferase 1 (DGAT1) to be essential for accumulation of triglyceride in necrotic TB granulomas using the C3HeB/FeJ murine model of infection. Treatment of infected mice with a pharmacological inhibitor of DGAT1 (T863) led to reduction in granuloma triglyceride levels and bacterial burden. A decrease in bacterial burden was associated with reduced neutrophil infiltration and degranulation, and a reduction in several pro-inflammatory cytokines including IL1β, TNFα, IL6, and IFNβ. Triglyceride lowering impacted eicosanoid production through both metabolic re-routing and via transcriptional control. Our data suggests that manipulation of lipid droplet homeostasis may offer a means for host directed therapy in Tuberculosis.
Highlights
Mycobacterium tuberculosis (Mtb), the causative agent for Tuberculosis in humans, is the leading cause of mortality due to a single infectious agent
We demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1) inhibition prevents neutral lipid accumulation in necrotic granulomas and leads to improved control of bacterial burden
Previous studies have revealed high heterogeneity in TB pathology in the C3HeB/FeJ mouse model, with only 50% of infected animals resulting in necrotic granulomas between days 28 and 42 post infection [20]
Summary
Mycobacterium tuberculosis (Mtb), the causative agent for Tuberculosis in humans, is the leading cause of mortality due to a single infectious agent. Even though treatment exists, infected individuals are at a life-long risk of poor lung function in case of pulmonary TB and debilitating morbidity in case of extrapulmonary TB [1]. Inflammation plays a significant role in these outcomes and host directed therapies that target inflammation and promote mycobactericidal activities of the host are sought in new treatment regimens [2]. Understanding the molecular events underpinning ensuing inflammation in the TB granuloma is key towards moving in this direction. Granulomas with necrotizing centers are hallmarks of tuberculosis in humans. Termed foamy macrophages, form a cellular cuff at the rim of these necrotic
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
