Virulence and Latency Regulation in M. tuberculosis

Type of Award: Catalyst
Date Awarded: June 2009
Award End Date: May 2011
Amount Awarded: $ 200,000.00
PI(s): Chuan He, PhD, UChicago; Scott Franzblau, PhD, UIC;

Abstract: It is estimated that one third of the world's population is infected with Mycobacteria tuberculosis (Mtb). In about 90% of infected people, Mtb persists throughout the life of the host in a largely non-replicating ("latent") state that causes no disease and against which antibiotics are ineffective. However, a change in the environmental conditions surrounding the bacterium (i.e. when the host becomes immune compromised) can make the bacterium exit the latent state and become pathogenic. Unfortunately, very little is known about the underlying molecular mechanisms and regulators that control the virulence and latency of Mtb. This proposal combines expertise from the Franzblau laboratory in the Institute of Tuberculosis Research (ITR) at the University of Illinois at Chicago (UIC) and the He laboratory from the University of Chicago (UofC) to address this fundamental question. We propose that reactive oxygen species (ROS) produced by host immune systems is a key signal that is sensed by Mtb and affects virulent states of the pathogen. Our proposed study will provide systems level and mechanism level understanding of the regulatory pathways involved in virulence and latency regulation in Mtb. This new knowledge will lead to a paradigm shift for how we treat Mtb infections: instead of screening for traditional bactericidal or bacteriostatic antibiotics that are less effective against Mtb in the latent state we may develop compounds that can either shut down the virulence of Mtb or activate exit of Mtb from the latent state and then eliminate the active forms with existing antibiotics that work well against actively replicating bacilli.