Stallings Lab Research

Our laboratory focuses on molecular pathogenesis and specifically involves characterization of the adaptation of Mycobacterium tuberculosis to host-inflicted stresses and persistent infection. At least 30% of the world’s population is infected with latent M. tuberculosis, which in some individuals will reactivate and cause an estimated 1.8 million deaths a year. This health crisis is exacerbated by the alarming emergence of multi-drug and extensively drug resistant strains. The inadequacies of present Tuberculosis therapies demand the discovery of new agents to treat M. tuberculosis infection, which requires insight into the pathways involved in M. tuberculosis pathogenesis. The general approach of our laboratory is to integrate in vivo disease modeling, molecular biology, and biochemistry to provide answers to the fundamental biological questions regarding molecular pathogenesis and yield therapeutic strategies for treatment of mycobacterial infections.

M. tuberculosis infection begins when inhaled bacilli enter the airways and are immediately exposed to phagocytic cells of the innate immune system. Infection of naive alveolar macrophages and dendritic cells leads to a proinflammatory response and the recruitment of lymphocytes, monocytes, and fibroblasts 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.

We have identified mycobacterial CarD as a mediator of mycobacterial stress responses as well as essential for acute and persistent infection. CarD depletion leads to sensitivity to killing by a range of stresses, accompanied by failure to reduce rRNA transcription, highlighting the importance of regulating rRNA levels to survive. The success of M. tuberculosis is attributed in part to its ability to control cell growth in the host and rRNA transcription is also closely coupled to cell growth rate. Despite the importance of this fundamental cellular process, the mechanisms of controlling rRNA transcription during mycobacterial pathogenesis are underinvestigated.

To shed light on these topics, our lab pursues the following research directions:

      1. Investigation of CarD’s mechanism of action and related pathways

      2. Dissection of the strategies and importance of rRNA transcription regulation during M. tuberculosis pathogenesis

      3. Identification of novel factors involved in mycobacteria stress responses important for infection

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