Grant: Operating Grant - Priority Announcement: Infection and Immunity (Bridge Funding)

Mycobacterium tuberculosis (mtb) is the causative agent of Tuberculosis (TB) and is considered to be the leading cause of death from a single organism in the world. Understanding how the disease works in the body is crucial for developing effective therapies to treat this deadly disease. Mtb primarily infect human white blood cells called macrophages, which represent the first line of cellular defense against microbial invasion. Our research is focusing on understanding how Mtb senses its surroundings enabling it to adapt to the hostile environment of the macrophage. We have previously shown that a family of proteins is essential for the physiology and virulence of the bacterium. One of the proteins, PtpA, is required for "successful" infection of macrophages. We had shown that PtpA acts by alteration of the white blood cells "normal" signaling mechanisms. Other members of this family are proposed to control key metabolic pathway in the bacterium enabling it to adapt to its host environment and to control the shift between growth and latency. The objective of this research is to further investigate the role, and mechanism of action of this protein and another member of the "eukaryotic-like" family of protein kinases and phosphatases, PknG. We will reveal the networking and signal transduction pathways within this bacterium and between it and the human macrophage host. We will also study the secretion mechanism of PtpA and Pkng and the role of a novel kinase we discovered recently for Mtb physiology. By examining these internal and external signaling pathways new therapies can be sought that will eventually improve the health of millions of people worldwide that suffer from TB.