We study the pathogenesis of tuberculosis and are interested in both the microbial and host factors contributing to this complex infection. Mycobacterium tuberculosis, the causative organism resides within macrophages of infected hosts and elicits the formation of granulomas, organized collections of modified macrophages and lymphocytes. Infection with M. tuberculosis can result in a variety of outcomes ranging from rapid clearance, acute symptomatic infection, or asymptomatic persistence (latent infection) that can reactivate.
We use a Mycobacterium marinum-zebrafish model. M. marinum is a close genetic relative of M. tuberculosis that causes tuberculosis in fish, frogs, and other ectotherms. M. marinum offers the advantages of a multiplicity of natural animal hosts that can be studied in the laboratory, relative safety, rapid growth, and easy amenability to genetic and cell biological approaches. We study infection in the zebrafish, a genetically tractable natural host to M. marinum. Zebrafish embryos are optically transparent so that we can monitor host-pathogen interactions in real-time to identify the exact steps of pathogenesis. Embryos represent a developmental stage when only innate immunity is operant so that we can discern the relative contribution of innate and adaptive immunity to infection.
We are particularly interested in the host and bacterial factors contributing to granuloma formation. We have identified bacterial factors that influence granuloma formation and find that the bacteria actually exploit granulomas considered to be host defenses for their proliferation and dissemination. Similarly, to determine the contribution of individual host genes to pathogenesis, we are using anti-sense oligonucleotide technology to inactivate individual host genes. Finally, we are conducting forward genetic screens in the zebrafish to identify new host genes that determine the outcome of infection.
