Research SummaryIntermediate Fellowship research summary
Lipid rich granulomas comprising of acellular necrotic caseum as well as lipid droplet rich macrophages are a hallmark of an active human tuberculosis infection. How this excess lipid affects the host and bacterial physiology is important to understand in order to develop effective treatment strategies against active TB infection. Recent work in the field has demonstrated challenges in targeting the pathogen, M. tuberculosis, when present within these lipid rich granulomas. The primary research interests of my lab are focussed on understanding how M. tuberculosis adapts to a lipid rich environment and the processes that govern host lipid homeostasis. We have recently demonstrated that M. tuberculosis physiology shifts towards an increase in metabolic activity on fatty acids, and is able to store excess host derived fatty acids as triglyceride when it encounters a triglyceride rich host environment (cover page, Infection and Immunity June 2018). Importantly, the lipid rich environment provides cues for the bacteria to become resilient to oxidative stress. This work will help in identifying pathways which can be targeted to increase susceptibility of the bacilli to antibiotics and host directed therapies. We also study how host neutral lipids can be altered and what effect it would have on bacilli. Lipid droplets being the host's sentinel for fatty acids, we questioned how their abundance and size changes during infection. Using a series of cellular biochemistry experiments, we demonstrated that acute infection of macrophages leads to lipolysis of fatty acids from triglycerides (BioRxiv https://doi.org/10.1101/187104). By studying the lipid droplet proteome during infection, we aim to understand this process. We have demonstrated that besides providing lipids to intracellular Mtb, lipid droplets are important in the inflammatory response to infection (published in Frontiers in Immunology in June 2018). Therefore, understanding how lipid droplets are manipulated during infection will provide means of targeting bacterial physiology and modulating the detrimental immune response in tuberculosis.
Figure Legend: Confocal z-stacks of mycobacteria (green) in the process of infecting an adipocyte (lipid droplets stained with anti-Perilipin antibody; red)