David M. Tobin
Host-Pathogen Interactions in Tuberculosis
Tuberculosis kills more than 1.5 million people annually. We aim to understand the intricate interplay between mycobacteria and their hosts using a combination of zebrafish genetics, human genetics 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 tuberculosis.
A zebrafish model of tuberculosis
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 immune responses.
Regulation of host eicosanoids in zebrafish and humans
Using these approaches, we focus on an important immunoregulatory pathway that controls susceptibility to tuberculosis by modulating pro- and anti-inflammatory eicosanoids. We have shown that genes identified in the zebrafish model are also important in human tuberculosis. Human variants in the leukotriene A4 hydrolase (LTA4H) gene are associated with susceptibility to both tuberculosis and leprosy. Additionally, we have found that these variants control the balance of pro and anti-inflammatory eicosanoids and that therapies directed at specific LTA4H genotypes in zebrafish and in humans result in genotype-dependent outcomes during mycobacterial infection.
Constructing the tuberculous granuloma
The granuloma, composed of interdigitated macrophages and other immune cells, is the central structure of tuberculosis. We use the zebrafish model to examine in subcellular detail and in real time the dynamics and pathways that are accessed during granuloma formation. We have developed a toolkit for rapid expression of gene products in a variety of specific immune cells. We are using these tools to specifically probe the granuloma, a structure that can restrict infection but that also plays a key early role in bacterial proliferation and dissemination. By understanding and manipulating the tuberculous granuloma, we hope to examine new strategies for anti-TB therapies.