Mycobacterium tuberculosis infection results in more deaths a year than any other single pathogen. There is a dire need to develop new therapeutics to treat these infections, which requires a better understanding of M. tuberculosis pathogenesis. M. tuberculosis infection begins when inhaled bacilli enter the airways and are phagocytosed by resident alveolar macrophages and dendritic cells, leading to a proinflammatory response and the recruitment of immune cells to form a granuloma. Within the granuloma, the infected cells are activated to kill the intracellular bacteria by imposing an arsenal of stresses. Despite this onslaught of stresses, the bacteria are able to persist for the lifetime of the host, indicating that M. tuberculosis mounts a significant defense against the immune system.

In the Stallings Laboratory, we dissect the molecular details of M. tuberculosis pathogenesis, from the perspective of both the host and the pathogen. We use a combination of genetics, biochemistry, cell biology, and animal models of disease to seek better understanding of how M. tuberculosis defends itself against host immune attacks and antibiotic therapy as well as what immune responses are required to control M. tuberculosis infection. We have identified a number of mycobacterial proteins that function as mediators of mycobacterial stress responses and are required for pathogenesis. In particular, we are currently focusing on how regulation of gene expression, DNA replication, and respiration allow M. tuberculosis to adapt to host-derived stresses and antibiotic therapy. In addition, we have discovered multiple host proteins and immune pathways that are required to control M. tuberculosis infection and prevent active tuberculosis disease. In particular, our studies highlight the importance of the innate immune response in regulating neutrophil-predominated inflammation to prevent tissue damage. In addition to these mechanistic studies, the lab is working to apply our basic science findings to the treatment of disease in humans.