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Cambridge Immunology Network

 

Lalita Ramakrishnan, M.B.B.S., Ph.D.
Professor, Immunology and Infectious Diseases

Research

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.

Publications

Key publications: 

            

Research Papers and Review Articles

Roca FJ, Whitworth LJ, Redmond S, Jones AA, Ramakrishnan L. TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit. Cell. 2019 Sep 5;178(6):1344-1361.e11. doi: 10.1016/j.cell.2019.08.004. Epub 2019 Aug 29. PubMed PMID: 31474371; PubMed Central PMCID: PMC6736209.

Behr MA, Edelstein PH, Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ. 2018 Aug 23;362:k2738. doi: 10.1136/bmj.k2738. PubMed PMID: 30139910; PubMed Central PMCID: PMC6105930.

A.J. Pagan, L. Ramakrishnan 2018. The formation and function of granulomas. Annu Rev Immunol Apr 26;36:639-665 https://doi.org/10.1146/annurev-immunol-032712-100022
 

iBiology talk on Tuberculosis Pathogenesis - https://www.ibiology.org/human-disease/tuberculosis-pathogenesis/

Madigan CA, Cambier CJ, Kelly-Scumpia KM, Scumpia PO, Cheng TY, Zailaa J, Bloom BR, Moody DB, Smale ST, Sagasti A, Modlin RL, Ramakrishnan L. A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell. 2017 Aug 24;170(5):973-985.e10. doi: 10.1016/j.cell.2017.07.030. PubMed PMID: 28841420; PubMed Central PMCID: PMC5848073.

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 doi:10.1016/j.immuni.2017.08.003

C. A. Madigan, J. Cameron, L. Ramakrishnan. 2017. A zebrafish model of Mycobacterium leprae granulomatous infection. J Infect Dis 16:776-779 doi:10.1093/infdis/jix329

Teaching and Supervisions

Research supervision: 
  • Antonio Pagán, Postdoctoral Fellow
  • Michal Eisenberg-Bord, Postdoctoral Fellow
  • Naoya Yamaguchi, Postdoctoral Fellow
  • Kevin Takaki, Senior Research Scientist
  • Jonathan Shanahan, Research Associate
  • Katie Shanahan, Research Associate
  • Adam Fountain, PhD Student
  • Nathan Usher, PhD Student
  • Bingnan Lyu, PhD Student
  • Janice Wong, Research Assistant
  • Joana Milao, Research Assistant
  • Lucinda Wood, Group Administrator
  • Laura Whitworth, Group Laboratory Manager