For the past several years encompassing her PhD and post-doctoral periods, Naeha Subramanian’s research interest has been the molecular mechanisms of innate immunity. She earned her PhD in immunology from the National Institute of Immunology in New Delhi, India. During this time she investigated the innate immune response to Salmonella typhi and found that during interaction with intestinal epithelial cells, S. typhi are stimulated to secrete monomeric flagellin in response to host-derived lysophospholipids. The de novo synthesized flagellin triggers innate immunity by engaging toll like receptor (TLR) 5. This work revealed a heretofore undescribed pathway in which the host signals the pathogen to synthesize a TLR ligand and earned her the G.P. Talwar Medal for Best PhD thesis (Subramanian and Qadri, Nat. Immunol. 7:583, 2006). Prior to her doctoral work, she completed an undergraduate degree in microbiology and M.Sc. in biomedical science from University of Delhi.
Aware of the need to apply sophisticated technologies to the study of innate control of microbial infections and with a desire to work on the newly discovered family of cytosolic sensors, the NLRs (nucleotide oligomerization domain, leucine-rich repeat, receptors), she began a postdoctoral fellowship with Dr. Ronald Germain at the National Institute of Allergy and Infectious Diseases (NIAID), NIH in 2007 as part of a new initiative in systems biology of immunology and host-pathogen interactions. The most well-recognized role of NLRs is as sensors of pathogens or tissue damage. In addition, gain of function mutations as well as polymorphisms in NLRs are associated with a host of severe human autoinflammatory and autoimmune disorders.
Naeha’s post-doctoral work offered new insights into several aspects of NLR function. Using a combination of sub-cellular imaging and biochemistry, she showed that mitochondria play a crucial role in assembly of the NLRP3 inflammasome. A key feature of this finding was that NLRP3 associates with mitochondria upon activation and such recruitment was promoted by the mitochondrial adapter protein MAVS. This was contrary to the prior belief that NLRP3 inflammasome assembly occurs in the cytosol. Her data change the prevailing inflammasome model from one involving a single adapter protein to one in which at least two adapters (ASC and MAVS) are required for optimal response to non-crystalline activators (Subramanian et al, Cell, 153, 348–361, 2013). She has also been involved in studying the role of calcium and cAMP as molecular regulators of NLRP3 activation (Nature, 492: 123, 2012), and the role of inflammasome-dependent cytokines IL-1b and IL-18 in orchestrating acute innate immune responses against intra- and extra-cellular pathogens in the lymph node (Cell, 150: 1235, 2012). Finally, as a step toward understanding the molecular basis of immune disorders, she was involved in studying signaling abnormalities in leukocyte subsets resulting from gain-of-function genomic deletions in PLCG2 (Phospholipase C γ2) (N. Engl. J. Med., 366: 330, 2012). This study deciphered the pathophysiologic cause of PLAID (Phospholipase Cγ2-associated Antibody deficiency and Immune Dysregulation), a novel disorder of immune dysregulation, and was recognized with the NIAID Merit Award (2011) and the NIH Director’s Award (2012).
Naeha joined the ISB faculty as Assistant Professor in March 2014 and is the newest addition to the faculty.
PhD, Immunology, National Institute of Immunology, New Delhi
Immunology, Innate Immunity, Host-Pathogen Interactions
Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. 2013. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation..Cell. 153(2):348-61.
Lee G-S, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJin. 2012. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP.. Nature. 492(7427):123-7.
Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P,Subramanian N, Bunney TD, Baxendale RW, Martins MS et al.. 2012. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.. N Engl J Med. 366(4):330-8.
Kastenmüller W, Torabi-Parizi P, Subramanian N, Lämmermann T, Germain RN. 2012. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread.. Cell. 150(6):1235-48.
Kastenmüller W, Gasteiger G, Subramanian N, Sparwasser T, Busch DH, Belkaid Y, Drexler I, Germain RN. 2011. Regulatory T cells selectively control CD8+ T cell effector pool size via IL-2 restriction.. J Immunol. 187(6):3186-97.
Subramanian N, Qadri A. 2006. Lysophospholipid sensing triggers secretion of flagellin from pathogenic salmonella.. Nat Immunol. 7(6):583-9.