Grant: Operating Grant

One third of the world's population is infected with tuberculosis (TB). Despite massive immunization campaigns a further 100 million new infections and 2 million deaths occur each year. Moreover, the last decade has seen the rise of drug- resistant TB, which has amplified this public health problem in many countries. Clearly, the current vaccine and drug regimens are inadequate. TB is notoriously difficult to treat because it has evolved to evade the killing mechanisms of the immune system. Typically, invading TB bacteria are engulfed by cells called macrophage, the "scavengers" of the immune system that patrol the body, ingesting and killing invading bacteria. But rather than being killed, TB bacteria takes up residence inside the macrophage. Somehow, it can attenuate multiple steps of our usual anti-bacterial defenses, allowing it to survive within the macrophage. Our goal is to investigate the underlying mechanisms in this process, in order to identify biologically-relevant targets for TB drug design. Our research shows that the TB bacteria produces and secretes key proteins into the host macrophage, which then interfere with intracellular killing mechanisms. In this proposal, we will investigate two such proteins - LpdC and Ndk - to determine how they allow TB bacteria to survive within the macrophage. We will use established cell and molecular biology techniques to address the following questions: 1) How do LpdC and Ndk protect the bacterium from macrophage killing mechanisms? 2) To what extent do LpdC and Ndk help the bacterium to persist in the lung? 3) If the genes that encode the proteins LpdC and/or Ndk are blocked (a "knock out"), does it transform a disease-causing mycobacteria into protective vaccines?