Grant: Project Grant

Tuberculosis (TB), a contagious respiratory disease of the lung caused by inhaling the bacterium Mycobacterium tuberculosis (Mtb) is responsible for over 2 million deaths each year, establishing it as one of the leading causes of infectious disease-related deaths worldwide. Inhaled Mtb are engulfed by special cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to deprive their killing ability, allowing the bacteria to remain hidden from the immune response and protected from drug therapy while inside these cells. Host-directed therapy, which targets host cell proteins rather than the bacteria itself offers a promising alternative treatment for TB as this strategy will circumvent development of antibiotic resistance and the need for drugs to penetrate the impermeable Mtb cell wall. We have identified PPM1A as critical host protein produced by macrophages that is exploited by Mtb to shut down the killing function of these immune cells. In this proposal, we will (1) elucidate the mechanisms regulating PPM1A expression during Mtb infection, and (2) characterize PPM1A associated signaling proteins that allow the bacteria to survive inside the cell. These approaches will identify and characterize key host proteins involved in the PPM1A signaling pathway that could be targeted for host-directed TB therapy. Finally, we will (3) examine the feasibility of targeting PPM1A to restore and improve the ability of macrophages to kill Mtb in vivo. This research will advance host-directed therapies aimed at eliminating TB.