Lalita Ramakrishnan, M.D., Ph.D.
University of Washington School of Medicine

Bacterial and Host Contributions to the Maintenance of the Granuloma in Tuberculosis Infections.

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. In this milieu, the organism is able to persist for decades without causing disease. One-third of the world's population is infected with M. tuberculosis in this so-called latent state. In a small proportion of infected individuals, the infection re-activates to cause serious disease commonly called active tuberculosis. Tuberculosis remains the single largest infectious cause of death world-wide.

We study mycobacterial pathogenesis using Mycobacterium marinum, a close genetic relative of M. tuberculosis that causes a tuberculosis-like disease in frogs, fish and other cold-blooded animals. It also replicates in cultured mammalian macrophages using strategies identical to those of M. tuberculosis. 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 have developed a technique called Differential Fluorescence Induction (DFI) to identify genes expressed only when the organism is within the host granuloma. A subset of these genes is also expressed in cultured macrophages. Some of these genes have been mutated in M. marinum and found to be important for organismal persistence in granulomas and/or cultured macrophages. Other DFI screens could be designed to uncover additional aspects of gene regulation in disease progression, e.g., from the persistent to the re-activated state.

We are currently studying the mechanistic basis of the role of this new class of host-induced virulence determinants using a combination of genetic, biochemical and cell biological approaches. The regulation of these genes is shedding light on the complex and ill-understood environment of the host granulomatous response to this infection both from an immunological and metabolic standpoint. We are trying to understand the relative roles played by the bacteria and the host in the maintenance of persistent (latent) infection.

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