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 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 larvae are optically transparent so that we can monitor host-pathogen interactions in real-time to identify the exact steps of pathogenesis.
By using a combination of forward and reverse genetics in the zebrafish coupled to genetic manipulations of M. marinum, we have made three surprising discoveries about TB. These fundamental discoveried have immediate clinical implications:
1) The tuberculous granuloma is a structure that is induced by the pathogen for its expansion and dissemination, a finding that counters its nearly hundred year old designation as the host-protective structure that walls off the bacteria to curtail infection. We are identifying ways to modulate the granuloma so as to benefit the host.
2) Drug tolerance in TB that leads to the requirement for 6-9 months of treatment has been attributed to the bacteria becoming dormant within the host. We have identified a mechanism wherein actively replicating bacteria become drug-tolerant through the in vivo induction of bacterial efflux pumps that primarily serve as bacterial virulence determinants. These drug-tolerant bacteria surviving treatment are also expanded and disseminated by the granuloma even during the course of treatment.
3) TB is a disease of both too little and too much inflammation. While TB has long been considered a disease of failed inflammation, we have identified pathways of increased inflammation governed by common human genetic variants that also lead to susceptibility. The hyperinflammatory form of TB requires distinct adjunctive treatments from the hypoinflammatory form and we are systematically idenifying the components of the pathway and drugs that will intercept them.
