To better understand and improve how the immune system kills antigen, we focus on M. tuberculosis (Mtb) and the host’s interaction with it. There are two reasons for this choice. First, Mtb is one of a small number of pathogens that live almost exclusively in humans. This means that Mtb has evolved both to withstand and to exploit human immunity, about which it must have a great deal to teach us. Second, Mtb is the leading cause of death from a bacterial pathogen. This is despite tuberculosis being a disease that was routinely curable. Today a growing number of cases are becoming incurable because of drug resistance. Juxtaposed, these facts speak of urgent medical need and the failure of conventional approaches to how drugs are discovered and deployed.
To the immunologist, Mtb presents a paradox that should be highly informative. Mtb typically elicits what is perhaps the most robust and well-rounded immune response of any known pathogen, yet avoids elimination by a large proportion of the people it infects. Host immunity drives the tissue pathology that sends Mtb forth in infectious droplets from the coughing host. Yet to spread the disease, Mtb must survive the immune response that was powerful enough to liquefy lung.
Our efforts to understand Mtb’s persistence in the face of host immunity have revealed multiple layers of the bacterium’s defense: suppression of selective aspects of host immunity; catabolism of toxic host molecules; repair of the damage that host immune chemistries inflict on the bacterium; degradation of bacterial macromolecules too damaged to be repaired; sequestration of macromolecules too damaged to be degraded; and descent into a state of dormancy in which the bacillus makes as little use as possible of its metabolic machinery while waiting for conditions to improve. We seek bacterial enzymes that mediate these processes and small molecules that inhibit those enzymes. Such compounds complement genetic and biochemical approaches for characterizing the functional significance of these resistance pathways and assessing their relevance for drug development.
Most projects in the lab today fall into one or more of the following broad topics: host pathways controlling susceptibility and resistance to Mtb; biology of Mtb in non-replicating states; and approaches to overcome the phenotypic resistance of non-replicating Mtb to most antibiotics by developing new kinds of antimicrobial molecules.
These campaigns call on disciplines ranging from immunology and microbiology to biochemistry and medicinal chemistry. Reflecting that, the lab is multi-disciplinary and highly collaborative. Much of our work with academic and industrial partners takes place via the Bill & Melinda Gates Foundation TB Drug Accelerator and the NIH-funded Tri-Institutional TB Research Unit (C. Nathan, Principal Investigator).