We are interested in understanding the pathogenesis of tuberculosis and the basis of vastly different susceptibilities to this disease. Tuberculous infection results in the formation of granulomas, complex immune structures that are composed of differentiated macrophages, lymphocytes and other immune cells. However, bacteria can persist within granulomas despite the development of antigen-specific immunity. To understand the mechanistic basis of mycobacterial persistence, the mechanisms of granuloma formation and its role in tuberculosis, we have developed the zebrafish as model to study immunity to tuberculosis. Zebrafish are naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of M. tuberculosis, the agent of human tuberculosis. We exploit the optical transparency and genetic tractability of the zebrafish to monitor the infection process in real-time and modulate it using genetically defined host and bacterial mutants. We have employed both forward and reverse genetics to understand the basis of host resistance and susceptibility to TB. Our research is shedding light on TB pathogenesis as well as fundamental mechanisms of immune cell chemotaxis, adhesion and aggregation as well as immune regulation. Detailed information about the sequential interactions among the host and the pathogen, the cell types, and the molecules involved has yielded surprising insights into this ancient disease. We have identified a number of host evasion strategies deployed by pathogenic mycobacteria as well as host responses that provide broad insights into host immunity. Findings made in the zebrafish have been borne out in human populations and are informing new strategies for intervention.
Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CL, Ramakrishnan L. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature. 2014 Jan 9;505(7482):218-22. doi: 10.1038/nature12799. Epub 2013 Dec 15.
Roca FJ, Ramakrishnan L. TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell. 2013 Apr 25;153(3):521-34. doi: 10.1016/j.cell.2013.03.022. Epub 2013 Apr 11.
Yang CT, Cambier CJ, Davis JM, Hall CJ, Crosier PS, Ramakrishnan L. Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages.
Cell Host Microbe. 2012 Sep 13;12(3):301-12. doi: 10.1016/j.chom.2012.07.009.
Takaki K, Cosma CL, Troll MA, Ramakrishnan L. An in vivo platform for rapid high-throughput antitubercular drug discovery.
Cell Rep. 2012 Jul 26;2(1):175-84.
Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King MC, Serhan CN, Ramakrishnan L. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.Cell. 2012 Feb 3;148(3):434-46. d
Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell. 2011 Apr 1;145(1):39-53.
Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND, Hagge DA, Khadge S, King MC, Hawn TR, Moens CB, Ramakrishnan L. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell. 2010 Mar 5;140(5):717-30. doi: 10.1016/j.cell.2010.02.013.
Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science. 2010 Jan 22;327(5964):466-9.
Davis JM, Haake DA, Ramakrishnan L. Leptospira interrogans stably infects zebrafish embryos, altering phagocyte behavior and homing to specific tissues. PLoS Negl Trop Dis. 2009 Jun 23;3(6):e463. doi: 10.1371/journal.pntd.0000463.
Brannon MK, Davis JM, Mathias JR, Hall CJ, Emerson JC, Crosier PS, Huttenlocher A, Ramakrishnan L, Moskowitz SM. Pseudomonas aeruginosa Type III secretion system interacts with phagocytes to modulate systemic infection of zebrafish embryos. Cell Microbiol. 2009 May;11(5):755-68. doi: 10.1111/j.1462-5822.2009.01288.x. Epub 2009 Jan 15.
Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009 Jan 9;136(1):37-49.