Research
In the continuous dialogue between an infected host and the invading pathogen, responses can be graded to achieve either co-habitation or destruction of either. This tug of war involves a fine balance of immune mediators such as cytokines, chemokines, lipid mediators, and metabolites against the ability of the pathogen to adapt to host derived stress. Mycobacterium tuberculosis is peculiar in that while it can persist in its host latently, it can also cause aggressive tissue damage in pulmonary and extra-pulmonary sites.
We are interested in studying the metabolic nexus of this host-pathogen interaction. The effect of the metabolic state of the host cell on the bacteria and vice versa are questions that we address in our lab using a multidisciplinary approach of bacterial genetics, cell biology, and biochemistry. Lipid droplets and lipid metabolism are central to our research interests.
Capturing host-pathogen interaction
We use live cell confocal imaging in M. bovis BCG infected cells and a wide range of tools including confocal and super-resolution microscopy in M. tuberculosis infected cells to understand the intracellular survival strategies of the bacteria and the host's response to infection. We focus on lipid droplet homeostasis in infection using biochemical and microscopy based methods.
Check out our previous work where we describe that host cell necrosis during M. tuberculosis infection drives a pro-inflammatory response in Tuberculosis via formation of foamy macrophages (https://www.frontiersin.org/articles/10.3389/fimmu.2018.01490/full.) We identified a role for the macrophage enzyme diacylglycerol O-acyltransferase , responsible for triglyceride synthesis, in driving the inflammatory response to infection. This work has opened up a new series of investigations trying to understand the role of triglycerides and lipid droplets in control of inflammation. Recent follow up work in the susceptible mouse model of tuberculosis revealed that triglyceride synthesis mediated inflammatory response offers a pro-pathogen niche for bacterial growth (https://www.frontiersin.org/articles/10.3389/fimmu.2021.722735/full).
A proteomic analysis of lipid droplets from infected macrophages allowed us to discover that these lipid droplets can be actively manipulated by the bacilli (https://pubs.acs.org/doi/10.1021/acsinfecdis.8b00301). We are now studying the relevance of these changes in the infection process.
Modulating metabolic states
Key to our investigations is manipulation of mammalian cells to achieve metabolically distinct states. Infection in these metabolically distinct conditions allows us to investigate how the physiology of bacteria is attuned to that of the host. We use gene expression analysis and bacterial genetics to investigate bacterial adaptation strategies in these environments.
Check out our work where we describe the physiology of M. tuberculosis in a lipid rich necrotic environment (http://iai.asm.org/content/early/2018/04/03/IAI.00041-18). In this work we used adipocytes and preadipocytes as models of infection. Both cell tyopes could be infected with virulent mycobacteria, allowed growth of the bacilli, and underwent necrosis with the bacilli remaining attached to the cellular debris. We performed differential expression profiling, metabolic activity assessment, and lipid analysis of bacteria from these conditions to identify that (1) the lipid rich host environment provides higher iron availability to the bacilli, and (2) the bacilli have higher oxidative stress mitigation capacity in the lipid rich environment. Our data further links that fatty acids are able to reduce the bacterial cytosol but iron is not thereby dissociating iron overload from oxidative stress mitigation. However, the increased oxidative stress mitigation capacity led to increased resilience to a mutant that is susceptible to iron mediated toxicity. This work identified a macronutrient (fatty acid)-micronutrient (iron) relationship of the host which the bacilli adapted to by altering its cytosol redox potential. We are now interested in understanding how lipid metabolism of the bacteria helps in achieving this feat.
PhD students and postdocs who join the group have access to a world class BSL3 facility and animal house, confocal and super-resolution microscopy facility.