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Cambridge Immunology Network



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.


Key publications: 


Research Papers and Review Articles


M.A. Behr, P.H. Edelstein, L. Ramakrishnan. 2019. Is tuberculosis infection lifelong?. BMJ in press.


F.J. Roca FJ, L. Whitworth, S. Redmond, A.A. Jones, L. Ramakrishnan. 2019. TNF Induces Pathogenic Programmed Necrosis in Tuberculosis through a mitochondrial-lysosomal- endoplasmic reticulum pathway. Cell, 178:1344-1361.


M.A. Behr, P.H. Edelstein, L. Ramakrishnan. 2018. Revisiting the time table of tuberculosis. BMJ 362:k2738


K.N. Adams, A.K. Verma, R. Gopalaswamy, H. Adikesavalu, D.K. Singhal, S. Tripathy, U.D. Ranganathan, D.R. Sherman, K.B. Urdahl, L. Ramakrishnan, R.E. Hernandez. 2019. Diverse clinical isolates of Mycobacterium tuberculosis develop macrophage-induced rifampicin tolerance. J Infect Dis. 219:1554-1558.


R.E. Hernandez, L. Galitan, J. Cameron, N. Goodwin, L. Ramakrishnan. 2018. Delay of initial feeding of zebrafish larvae until 8 days postfertilization has no impact on survival or growth through the juvenile stage. Zebrafish. 15(5):515-518


A.J. Pagan and L. Ramakrishnan. 2018. The formation and function of granulomas. Ann Rev Immunol doi: 10.1146/annurev-immunol-032712-100022. [Epub ahead of print] PMID:29400999


K. Takaki and L. Ramakrishnan. 2018. A zebrafish model for ocular tuberculosis. PLoS One. 13(3):e0194982


C.J. Cambier, S.M. O'Leary, M.P. O'Sullivan, J. Keane, L. Ramakrishnan 2017.  Phenolic Glycolipid facilitates mycobacterial escape from microbicidal tissue-resident macrophages. Immunity 47:552 565


C. A. Madigan, J. Cameron, L. Ramakrishnan. 2017. A zebrafish model of mycobacterium leprae granulomatous infection. J Infect Dis 16:776-779


A.J. Pagan, L. Ramakrishnan. 2017. TORmented macrophages spontaneously form granulomas. Nat Immunol. Feb 15;18(3):252-253. doi: 10.1038/ni.3689


C.A. Madigan, C.J. Cambier, K.M. Kelly-Scumpia, P.O. Scumpia, T.Y. Cheng, J. Zailaa, B.R. Bloom, D.B. Moody, S.T. Smale, A. Sagasti, R.L. Modlin, L. Ramakrishnan. 2017. A macrophage response to Mycobacterium leprae phenolic glycolipid initiates nerve damage in leprosy. Cell 170:973-985.


W.H. Conrad, M.M. Osman, J.K. Shanahan, F. Chu, K.K. Takaki, J. Cameron, D. Hopkinson-Woolley, R. Brosch, L. Ramakrishnan. 2017.  Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions. Proc Natl Acad Sci USA. 114:1371-1376.


S. Levitte, K.N. Adams, R.D. Berg, C.L. Cosma, K.B. Urdahl, L. Ramakrishnan. 2016. Mycobacterial Acid Tolerance Enables Phagolysosomal Survival and Establishment of Tuberculous Infection In Vivo. Cell Host and Microbe 20:250-258


R.D. Berg, S. Levitte, M.P. O'Sullivan, S.M. O'Leary, C.J. Cambier, J. Cameron, K.K. Takaki, C.B. Moens, D.M. Tobin, J. Keane, L. Ramakrishnan. 2016. Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration. Cell 165:139-52.


A.J. Pagán, C-T. Yang, J. Cameron, L. E. Swaim, F. Ellett, G. J. Lieschke, L. Ramakrishnan 2015. Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment.  Cell Host Microbe 18. 15-26


C.J. Cambier , S. Falkow, L. Ramakrishnan. 2014. Host Evasion and Exploitation Schemes of Mycobacterium tuberculosis. Cell. 159:1497-1509.


A.J Pagán  and L. Ramakrishnan. 2014. Immunity and Immunopathology in the Tuberculous Granuloma Cold Spring Harb Perspect Med. PMID: 25377142


E.E. Patton, P. Dhillon, J.F. Amatruda, L. Ramakrishnan.  Spotlight on zebrafish: translational impact. Dis Model Mech 7:731-3.


L. Ramakrishnan. 2013. The zebrafish guide to tuberculosis immunity and treatment. Cold Spring Harb Symp Quant Biol. 78:179-92.


K.N Adams, J. Szumowski, and L. Ramakrishnan, 2014. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs. J Infect Dis 10.1093/infdis/jiu095


C.J. Cambier, K.K. Takaki, R.P. Larson, R.E. Hernandez, D.M. Tobin, K.B. Urdahl, C.L. Cosma, L. Ramakrishnan. 2014. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218-22


D.M. Tobin and L. Ramakrishnan 2013. TB: the Yin and Yang of lipid mediators. Curr Opin Pharmacol. 13, 641-5.

D.M. Tobin, F.J. Roca, J.P. Ray, D.C. Ko, L. Ramakrishnan. 2013. An enzyme that inactivates the inflammatory mediator leukotriene B4 restricts mycobacterial infection. PLoS One 11, e67828.

K.K. Takaki, J.M. Davis, K. Winglee, and L. Ramakrishnan. 2013. F.J. Roca and L. Ramakrishnan. 2013.  Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in the zebrafish. Nat Protoc 8, 1114-1124


F.J. Roca and L. Ramakrishnan. 2013. TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153, 521-534


L. Ramakrishnan. 2013.  Looking within the zebrafish to understand the tuberculous granuloma. Adv Exp Med Biol 783:251-266.


J.D. Szumowski, K.N. Adams, P.H. Edelstein and L. Ramakrishnan. 2012. Antimicrobial Efflux Pumps and Mycobacterium Tuberculosis Drug Tolerance: Evolutionary Considerations. Curr Top Microbiol Immunol PMID: 23242857


R.D. Berg and L. Ramakrishnan. 2012. Insights into Tuberculosis from the Zebrafish Model. Trends Mol Med 18:689-90.


C.T. Yang, C.J. Cambier, J.M. Davis, C.J. Hall, P.S. Crosier, L. Ramakrishnan. 2012 Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages. Cell Host Microbe 12: 301-312


K. Takaki, C.L. Cosma, M.A. Troll and L. Ramakrishnan. 2012. An in vivo platform for rapid high-throughput antitubercular drug discovery. Cell Reports 2:175-84.


L. Ramakrishnan. 2012. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 12:352-66.


D.M. Tobin, F.J. Roca, S.F. Oh, R. McFarland, T.W. Vickery, J.P. Ray, D.C. Ko, Y. Zou, N.D. Bang, T.T. Chau, J.C. Vary, T.R. Hawn, S.J. Dunstan, J. J. Farrar, G.E. Thwaites, M.C. King, C.N. Serhan, L. Ramakrishnan. 2012. Host Genotype Directed Therapies can Optimize the Inflammatory Response to Mycobacterial Infections. Cell 148:434-46.


K.N. Adams, K.K Takaki, L.E. Connolly, H. Wiedenhoft, K. Winglee, O. Humbert, P.E. Edelstein, C.L. Cosma, L. Ramakrishnan.  2011.  Drug Tolerance in Replicating Mycobacteria Induced by a Macrophage-Induced Efflux Mechanism.  Cell, 145, 39-53


D. M. Tobin, J.C. Vary Jr, J.P. Ray, G.S. Walsh, S.J. Dunstan, N.D. Bang, D.A. Hagge, S. Khadge, M-C. King, T.R. Hawn, C.B. Moens, L. Ramakrishnan. The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans.  2010. Cell 140:717-730. 


H. E. Volkman, T. C. Pozos, J. Zheng, J.M. Davis, F. Chu, J. F. Rawls, L. Ramakrishnan. 2010. Tuberculous granuloma induction via interactions of a bacterial secreted protein with host epithelium. Science, 327:466-469.


B.A. Traag. A. Driks, P. Stragier, W. Bitter, G. Broussard, G. Hatfull, F. Chu, K.N. Adams, L. Ramakrishnan, R. Losick. 2009. Do mycobacteria produce endospores? Proc Natl Acad Sci USA, 107:878-81.


J.M. Davis, D. Haake*, L. Ramakrishnan*. 2009 Leptospira interrogans stably infects zebrafish in embryos, altering phagocyte behavior and homing to specific tissues.  PLoS Neg Trop Dis, 3:e463. *Joint corresponding authors.


M. Brannon, J. M. Davis, C. Hall, P. Crozier, J. R. Mathias, A. Huttenlocher, L. Ramakrishnan* and S.  Moskowitz*. 2009. Pseudomonas aeruginosa Type III secretion system interacts with phagocytes to modulate systemic infection of zebrafish embryos.  Cell Microbiol, 11:755-768. *Joint corresponding authors.


J.M. Davis and L. Ramakrishnan.  2009.  The role of the granuloma in the expansion and dissemination of  early tuberculous infection.  Cell 136:37-49


C.L. Cosma, O. Humbert, D.R. Sherman. L. Ramakrishnan. 2008. Trafficking of Superinfecting Mycobacterium into Established Granulomas Occurs in Mammals and is Independent of the Mycobacterial Erp and ESX-1/RD1 Virulence Loci. J Infect Dis, 198:1851-5.


H. Clay, HE Volkman and L. Ramakrishnan. 2008.  TNF signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death but is not required for tuberculous granuloma formation. Immunity 29:283-294.


D.M. Tobin and L. Ramakrishnan. 2008. Comparative pathogenesis of Mycobacterium marinum and Mycobacterium tuberculosis. Cell Microbiol 10:1027-1039.


J.M. Davis and L. Ramakrishnan. 2008. "The very pulse of the machine": the tuberculous granuloma in motion. Immunity 28:146-148.


R.E. Lesley and L. Ramakrishnan. 2008.  Insights into early mycobacterial pathogenesis from the zebrafish. Curr Opin Microbiol, 11:277-283.


T.P. Stinear, T. Seemann, P.F. Harrison, G.A. Jenkin, J.K. Davies, P.D.R. Johnson, Z. Abdellah,  C. Arrowsmith,  T. Chillingworth,  C. Churcher, K. Clarke, A. Cronin, P. Davis, I.  Goodhead N. Holroyd, K. Jagels, A. Lord, S. Moule, K. Mungall, H. Norbertczak,  M.A. Quail, E. Rabbinowitsch, D. Walker, B. White, S. Whitehead, P.L.C. Small, R. Brosch, L. Ramakrishnan, M.A. Fischbach,  J. Parkhill and S.T. Cole. 2008. Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res 18:729-741.


H. Clay, J.M. Davis, D. Beery, A. Huttenlocher, S. E. Lyons and L. Ramakrishnan. 2007. Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host and Microbe 2:29-39.


L. E. Connolly, P.H. Edelstein and L. Ramakrishnan. 2007.  Why is long-term drug treatment needed to cure tuberculosis?  PLoS Medicine 4:e120.


L.E. Swaim, L.E. Connolly, H.E. Volkman, O. Humbert, D. E. Born, and L. Ramakrishnan. 2006. Mycobacterium marinum infection of adult zebrafish produces caseating granulomatous tuberculosis and is moderated by adaptive immunity. Infect Immun 74:6108-17.


C. L. Cosma, K. Klein, R. Kim, D. Beery, and L. Ramakrishnan. 2006 Mycobacterium marinum Erp is a virulence determinant required for cell wall integrity and intracellular survival. Infect Immun 74:3125-3133.


D. Fredricks and L. Ramakrishnan. 2006. The acetobacteraceae: extending the spectrum of human pathogens. PLoS Pathog 2:e36.


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


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


C.L. Cosma, O. Humbert, and L. Ramakrishnan.  2004.  Superinfecting mycobacteria home to established tuberculous granulomas. Nat Immunol 5:828-35.


T.C. Pozos and L. Ramakrishnan.  2004.  New models for the study of Mycobacterium-host interactions. Curr Opin Immunol 16:499-505.


L. Ramakrishnan. 2004. Using Mycobacterium marinum and its hosts to study tuberculosis. CurrScience 86:82-92.


C.L. Cosma, D.R. Sherman and L. Ramakrishnan. 2003. The Secret Lives of the Pathogenic Mycobacteria. Ann Rev Microbiol 57:641-76.


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.


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


D.M. Bouley, N. Ghori, K.L. Mercer, S. Falkow and L. Ramakrishnan.  2001.  The dynamic nature of the host-pathogen interactions in Mycobacterium marinum granulomas. Infect Immun 69: 7820-7831.


L. Ramakrishnan, N. Federspiel and S. Falkow.  2000.  Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288:1436-1439.


L. Ramakrishnan, H.T. Tran, N.A. Federspiel and S. Falkow. 1997. A crtB homologue essential for photochromogenicity in Mycobacterium marinum: isolation, characterization and gene disruption via homologous recombination. J Bacteriol 179: 5862-5868.


L. Ramakrishnan. 1997. Mycobacterium marinum infection of the hand.  New Engl Jour Med 337:612.


L. Ramakrishnan, R. H. Valdivia, J. McKerrow and S. Falkow. 1997. Mycobacterium marinum causes both long-term subclinical infection and acute disease in the leopard frog (Rana pipiens). Infect Imm 65:767-773.


L. Ramakrishnan and S. Falkow. 1994. Mycobacterium marinum persists in cultured mammalian cells in a temperature-restricted fashion. Infect Immun 62:3222-3229.


P. Small, L. Ramakrishnan and S. Falkow. 1994. Remodeling schemes of intracellular pathogens.  Science 263:637-639.


M. Linzer, B.P. Grubb, S. Ho, L. Ramakrishnan, E. Bromfield, N.A. Estes 3rd. 1994. Cardiovascular causes of loss of consciousness in patients with presumed epilepsy: a cause of the increased sudden death rate in people with epilepsy? Am J Med 96:146-154.


L. Ramakrishnan, Q. Wu, A. Yu, M.D. Cooper and N. Rosenberg. 1990. BP-1/6C3 expression defines a differentiation stage of transformed pre-B cells and is not related to malignant potential.  J Immunol 145:1603-1608.


L. Ramakrishnan and N. Rosenberg. 1989. abl genes. Biochem Biophys Acta 989:209-224.


L. Ramakrishnan and N. Rosenberg. 1988. Novel B cell precursors blocked at the stage of DJH recombination.  Mol Cell Bio 8: 5216-5223.



Book Chapters


D.A. Relman, S. Falkow, L. Ramakrishnan . 2020. A molecular perspective of microbial pathogenicity. In Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, ninth edition. Elsevier Press.


J.M. Davis and L. Ramakrishnan.  2009. The zebrafish as a model for studying phagocyte-pathogen interactions in vivo. In The multiple faces of the phagocyte.  ASM press.  Eds.  S. Gordon and D. Russell.  


C. L. Cosma, J. M. Davis, L. E. Swaim, H. Volkman, and L. Ramakrishnan.  2006. Zebrafish and Frog Models of Mycobacterium marinum Infection.  Curr Prot Microbiol, 10B.2.1-10B.2.33. John Wiley and Sons Inc.


L. Ramakrishnan and S. Falkow. 1999  Pathogen strategies: A hitchhiker’s guide to the macrophage. In Advances in Cell and Molecular Biology of Membranes and Organelles. Vol. 6, pp 1-25. Ed. S. Gordon, JAI Press Inc. Greenich CT. 


R.H. Valdivia and L. Ramakrishnan.  2000. Applications of GFP gene fusions and flow cytometry to the study of bacterial gene expression in host cells. In  Methods in Enzymology, Academic Press, San Diego, CA. Eds. J.N. Abelson, S.D. Emr and J. Thorner. 326, 47-73.




Professor Lalita  Ramakrishnan
Not available for consultancy