Faculty and Research
David Tobin, PhD
Tuberculosis: mycobacterial pathogenesis and host susceptibility
Tuberculosis kills almost two million people annually. Our laboratory aims to understand the intricate interplay between mycobacteria and their hosts using a combination of model organism genetics, human genetics, pharmacology and high-resolution microscopy. By identifying key pathways utilized by the infecting bacteria and the host innate immune system, we hope to discover new therapeutic targets and interventions to combat this enduringly destructive disease.
Using a Mycobacterium/zebrafish model, we have performed a forward genetic screen to identify new host susceptibility loci. Zebrafish are natural hosts to Mycobacterium marinum, the closest relative of the Mycobacterium tuberculosis complex. Because zebrafish embryos and larvae are optically transparent, we are able to visualize the complex details of mycobacterial pathogenesis in whole, live animals. The facile genetics of the zebrafish allow us to map and positionally clone affected host susceptibility genes. In addition, zebrafish larvae are remarkably permeable to small molecules, providing a platform for whole-animal pharmacological manipulation of specific host immune responses.
Using these approaches, we have identified a novel immunoregulatory pathway that controls susceptibility to tuberculosis by modulating pro- and anti-inflammatory eicosanoids. Finally, we have shown that genes identified in the zebrafish model are also important in human tuberculosis. We find robust associations of human variants in this pathway with susceptibility to both tuberculosis and leprosy.