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Lalita Ramakrishnan, M.D. 
Asstitant Professor of Microbiology and Medicine
CONTACT INFORMATION
University of Washington
Department of Microbiology
Box 357242, HSB K-443C
Seattle, Washington 98195
We study the pathogenesis of tuberculosis and are interested in both the microbial and host factors contributing to this complex infection and are interested in both microbiology and immunology.
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.
We are currently studying the mechanistic basis of the role of this new class of host-induced virulence determinants using a combination of genetic, 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 the standpoint of the host and the bacteria. We are trying to understand the relative roles played by the bacteria and the host in the maintenance of persistent (latent) infection and are trying to directly assess the metabolic and replicative state of the bacteria in vivo during latent infection.
We also study host responses to tuberculosis and are particularly interested in understanding the basis of the differential susceptibility to tuberculosis among different individuals. For this we exploit zebrafish which are genetically tractable and optically transparent. We can monitor host-pathogen interactions live in the optically transparent larvae. We can also manipulate host gene immune expression to identify their role in infection as well as perform genetic screens to identify new host susceptibility genes.
Cosma CL, Sherman DR, Ramakrishnan L. The Secret lives of the pathogenic Mycobacteria. Annual Rev Microbiol, in press.
Davis JM, Clay H, Lewis JL, Ghori N, Herbomel P, Ramakrishnan L. Real-time visualization of Mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos. Immunity 17:693-702, 2002.
Chan K, Knaak T, Satkamp L, Humbert O, Falkow S, Ramakrishnan L. Complex pattern of Mycobacterium marinum gene expression during long-term granulomatous infection. PNAS 99:3920-5, 2002.
Bouley DM, Ghori N, Mercer KL, Falkow S, Ramakrishnan L. The dynamic nature of the host-pathogen interactions in Mycobacterium marinum granulomas. Infect Immun 69:7820-31, 2001.
Ramakrishnan L, Federspiel N, Falkow S. Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288:1436-9, 2000.
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