M. tuberculosis (Mtb), causative agent of Tuberculosis (TB), is often hailed as the most 'successful' pathogen. WHO reports over 15 million new infections and 1.5 million deaths annually. The long treatment duration and rapid rise of antibiotic resistance makes treatment options for TB difficult necessitating new approaches in combating the disease. Mtb pathogenesis mechanisms in vivo and cellular correlates of virulence are poorly defined. In this talk, I will outline our current efforts to understand the pathogenesis mechanisms in vivo. Using chemical genetic approach, we target a host cellular pathway previously identified in our lab, namely lysosomal biogenesis, to manipulate Mtb survival in a mouse model. Pharmacological abrogation of lysosomes of the host renders hypersusceptibility to Mtb, while activation has the opposite effect, thus providing a tunable system to explore the spectrum of Mtb survival states in vivo. I will discuss the mechanistic basis of these observations and our current strategy to use the proinfective to tamper with Mtb dormancy in vivo.

key words: M. tuberculosis, in vivo, lysosomes, dormancy, reactivation