Our long-term goal is to elucidate host-pathogen interactions that govern the ability of Mycobacterium tuberculosis (Mtb) to cause disease in humans. We are taking an integrated approach, using powerful new molecular genetic, cell biologic, bioinformatic and metabolomic tools to test novel hypotheses and challenge existing paradigms. Our ultimate aim is to use this knowledge to develop new vaccines and treatments for Mtb (Fig. 1).
Discovering the routes of transmission, survival and escape of Mtb from its human host
Three key phases in a pathogen’s life cycle dictate its ability to cause disease, namely, i) invasion ii) survival and propagation and iii) escape beyond the host to infect naïve individuals. To date, how Mtb crosses the mucosa and enters the human body is incompletely understood. Likewise, the full repertoire of mechanisms used by Mtb to manipulate and persist within host macrophages is unknown. Additionally, our knowledge of macrophage antimicrobial mechanisms in host defense against Mtb and other pathogens remains incomplete. Enhancing such antimicrobial mechanisms via host-directed therapies is a promising new approach to Mtb treatment. Finally, how Mtb facilitates its own transmission through cough induction has not been studied. Thus, we are addressing these areas of Mtb biology through a series of hypothesis-driven approaches. First, how does Mtb penetrate the nasopharyngeal and respiratory mucosa to cause disease? Second, what are the mechanisms Mtb uses to manipulate host processes to facilitate survival? Third, can host antimicrobial pathways be leveraged to enhance the eradication of intracellular bacteria such as Mtb? Finally, how does Mtb trigger coughing to mediate its spread?