Mycobacterium tuberculosis host-pathogen interface
We are interested in the interface between intracellular bacterial pathogens and the hosts they infect. In particular, we study the notorious human pathogen, Mycbacterium tuberculosis, which remains a major global health threat. M. tuberculosis has evolved a variety of specific adaptations to not only survive but also replicate within the harsh environment inside a macrophage. We want to understand the mechanisms by which M. tuberculosis is able to modulate the innate immune response to establish an infection as well as how the host detects and responds to M. tuberculosis.
How is Mtb sensed within a macrophage?
Cytosolic DNA is an important "danger signal" that alerts macrophages and other host cells that they are infected by a intracellular pathogen. We are primarily focused on two major outcomes of cytosolic DNA sensing during M. tuberculosis infection: targeting of Mtb to autolysosomes by ubiquitin-dependent selective autophagy and activation of a type I IFN cytokine program. Interestingly, activation of these two pathways lead to opposite infection outcomes, with autophagy being required to control M. tuberculosis infection and type I IFNs exacerbating M. tuberculosis pathogenesis. Ultimately, by identifying the players involved in each of these pathways, we hope to one day develop host-directed therapeutics that can polarize DNA sensing outcomes in favor of the host.
To interrogate the biology occurring between M. tuberculosis and its host, we use a number of techniques, including immunofluorescence microscopy, cell culture infection, protein biochemistry, genetic manipulation of host cells (shRNA knockdown and CRISPR/Cas9 knockout), and in vivo infection using mutant mouse strains. We perform experiments using wild-type M. tuberculosis in biosafety level 3 containment facilities.