Thomas C. Zahrt, PhD

My research interests include the study of Mycobacterium tuberculosis and the mechanisms by which this organism establishes, maintains, and reactivates from persistent (latent) infection. To investigate these processes, our laboratory utilizes several Mycobacterial model systems and a variety of in vitro and in vivo techniques. Through these studies, we hope to identify determinants and pathways important for regulating survival of M. tuberculosis within the host.

One primary area of focus in the laboratory is the study of two-component signal transduction systems and the downstream determinants regulated by these systems. MprAB is a two-component system that mediates resistance to cell envelope stress and is required by M. tuberculosis for persistent infection within the host. More than 100 determinants are regulated by MprAB including two stress-responsive sigma factors (SigE and SigE), an HtrA-like serine protease (PepD), and genes encoding a predicted phage shock protein system (Psp). Interestingly, we have found that phage shock protein A (PspA), an important component of this system, binds intracytoplasmic lipid droplets when they are produced by Mycobacterium under conditions of stress. Lipid droplets are fatty acid storage compartments which contain a neutral fatty acid core and which are surrounded by a phospholipid monolayer and proteins. Lipid droplets are thought to be the primary energy source utilized by M. tuberculosis during latency when the bacterium exists within granulomatous lesion.

Our recent studies have demonstrated that PspA associates with lipid droplets using an amphipathic helix that is present at the N-terminus of the protein. Loss or overproduction of PspA alters the size distribution of lipid droplets produced, and negatively impacts the ability of Mycobacterium to survive under conditions of non-replicating persistence. Current studies are focused on understanding the molecular mechanism by which PspA regulates these activities and determining whether other proteins play a role in lipid droplet homeostasis and Mycobacterial persistence during latency.