How do macrophages kill TB? How does TB evade macrophage defenses?

Macrophages are the central player in TB pathogenesis as they serve both as the host cell for infection and the cell primarily responsible for killing bacteria.  Early after infection TB replicates extensively in macrophages, however when T cells arrive in the infected lungs, they activate microbicidal mechanisms of macrophages. One major mechanism by which T cells activate macrophages to control infection is by production of the cytokine IFN-γ. Surprisingly, we lack a complete understanding of the molecular mechanisms of macrophages that are activated by IFN-γ that result in direct killing of bacteria. One major focus of the lab is to identify new effector mechanisms activated by IFN-γ that facilitate successful control of infection using both hypothesis driven approaches and unbiased screening.  In newer projects, we are also examining IFN-γ independent mechanisms by which T cells activate macrophages to control infection.  Finally, although activation of macrophages can result in immune control, it rarely results in sterilization.  We also investigate the mechanisms by which bacteria are able to prevent clearance by these immune mechanisms.

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Metabolic regulation of the host-pathogen interaction

During infection Mtb is thought to exist along a spectrum of metabolic states, from active replication through a dormant non-replicating state. Mtb metabolism has a significant impact on the efficacy of antibiotics, as slowly replicating or dormant bacteria are very difficult to kill with conventional antibiotics. Macrophage metabolism is also important for the outcome of infection, as shifts in macrophage metabolism affect not only microbicidal mechanisms such as autophagy, but also affect the spectrum of nutrients available to the bacterium.  In vivo, Mtb is thought to rely on host lipids and cholesterol as primary carbon sources during infection.  We are interested in understanding the intersection between macrophage metabolism and bacterial metabolism, and use a variety of techniques ranging from bacterial and host genetics through metabolomics and proteomics to address these questions.

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Development of novel therapeutics and vaccine adjuvants

Our research is motivated by the need to find new interventions for treating and preventing infection with Mtb to support efforts for global eradication. One major area of emphasis is the discovery of host-targeted therapeutics that function to enhance the immune response to Mtb or inhibit virulence pathways to facilitate clearance of infection.  We use basic research to identify important pathways in the host that can be targeted by small molecules.