Lalita Ramakrishnan
Associate Professor of Microbiology

COS Profile
Email: lalitar@u.washington.edu
Phone:(206) 616-4286, (206) 221-6367
Office Location: Health Sciences K-443C
Campus Box: 357242

Research:

Dr. Ramakrishnan received her MBBS from Baroda Medical College, India and her PhD in immunology from Tufts University. She then did residency training in medicine at the New England Medical Center, Boston, fellowship training in infectious diseases at the University of California, San Francisco and a postdoctoral fellowship at Stanford University.

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.

Immunofluorescent laser confocal image of a granuloma from a frog persistently infected with M. marinum for one year. The bacteria are expressing a granuloma specific gene fused to a promoterless green fluorescent protein (gfp) gene. Activation of gene expression in the granuloma allows the gfp fusion to be expressed, rendering the bacteria green fluorescent.

Selected Publications:

K. Chan, T. Knaak, L. Satkamp, O.Humbert, S. Falkow and L. Ramakrishnan. Complex pattern of Mycobacterium marinum gene expression during long-term granulomatous infection. PNAS, 2002; 99:3920-3925.


J.M. Davis, H. Clay, J.L. Lewis, N. Ghori. P. Herbomel and L. Ramakrishnan. 2002. Real-time visualization of Mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos. Immunity 17:693-702.


C. L. Cosma, O. Humbert, and L. Ramakrishnan. 2004. Superinfecting mycobacteria home to established tuberculous granulomas. Nature Immunology, 5:828-835.


H. E. Volkmann, H. Clay, D. Beery, J.C.W. Chang, D. R. Sherman, and L. Ramakrishnan. 2004. Tuberculous granuloma formation is enhanced by a Mycobacterium virulence determinant. PLoS Biology, 2:1946-1956.


H. Clay and L. Ramakrishnan. 2005. Multiplex fluorescent in situ hybridization in zebrafish embryos using tyramide signal amplification. Zebrafish,2:105-111.