Subramanian Lab Overview
To understand the molecular basis of immune disorders, it is critical to understand the earliest – inborn or innate – events that initiate them and how they cause dysregulation of normal immune networks. That’s what drives my interest in applying a systems approach to understanding innate immunity.
–Assistant Professor, Dr. Naeha Subramanian
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The Subramanian Lab works in the fields of innate immunity and systems immunology. We employ experimental and computational approaches to tackle basic questions in innate immunity, its role in host defense against pathogens and the development of complex diseases. In particular, we are interested in exploring the functions and regulation of a class of cytosolic immune sensors called the NOD-like receptors (or NLRs) and how their dysregulation manifests disease. We apply the insights gleaned from this research to broadly address how the immune system goes awry in human immune disorders, and we develop strategies for therapeutic benefit.
Host-Pathogen Crosstalk: Pathogens and hosts are engaged in a constant evolutionary arms race. Macrophages are one of the earliest cell types that detect pathogens through cell surface-associated Toll-like receptors (TLRs) and mount an innate immune response. Inside macrophages, invading pathogens are detected by different classes of cytosolic sensors. These include the NLRs that form inflammasomes resulting in production of IL-1b, and the RIG-I like helicases that activate production of type 1 interferons. We are investigating the mechanisms by which intracellular pathogens like Salmonella and Mycobacterium adapt to the hostile innate immune microenvironment inside the macrophage. In particular, we have recently shown that Salmonella co-opts NLRC4 inflammasome activation to initially enhance production of its flagellin and promote systemic spread, and later on takes advantage of a type 1 interferon-dependent decrease in NLRC4 and host lysophospholipids to downregulate flagellin within macrophages and evade innate immune detection. Our findings provide one explanation for why people are more prone to secondary bacterial infections after enduring a primary viral infection.
The NLRP3 Inflammasome: We are investigating how the NLRP3 inflammasome is activated in response to diverse stimuli. NLRP3 is implicated in the pathophysiology of many autoinflammatory, autoimmune, metabolic and infectious diseases. NLRP3 is activated by a wide-range of molecules including crystals formed in gout and atherosclerosis, viruses and bacterial toxins, but the mechanisms by which NLRP3 senses and elicits a response to these chemically and structurally dissimilar stimuli remain elusive. We are investigating the role of mitochondrial and other subcellular structures in NLRP3 inflammasome activation and how this key organelle controls not only NLRP3 inflammasome activity but also other innate sensing pathways converging on the mitochondria. These questions follow from our previous work showing that mitochondrial recruitment of NLRP3, increased cytoplasmic calcium and decreased cyclic AMP are important early events in NLRP3 inflammasome activation.
Systems Biology of NLRs: In humans, 23 NLRs have been identified. These have been hypothesized to have distinct biological functions based on sequence and structure modeling analysis. To date, however, only a few NLRs have been studied intensively and the activating stimuli, physiologic functions, and relevant signaling pathways of most members of the NLR family are unknown or poorly defined. Genetic mutations and polymorphisms in NLRs are associated with a host of severe human autoinflammatory and autoimmune disorders, ranging from rare hereditary periodic fever syndromes (NLRP3) and early-onset sarcoidosis (NOD2) to more common disorders such as rheumatoid arthritis (CIITA), vitiligo (NLRP1), inflammatory bowel diseases (NOD1 and NOD2) and gastric cancer (NOD1), to name a few. We are undertaking systems-level approaches to understand NLR signaling pathways, their regulation, and the diseases resulting from NLR dysfunction. Our recent work has shown that a small sustained increase in NOD1 expression triggers ligand-independent inflammatory and oncogene responses providing insight into how a quantitatively small change in protein abundance can produce marked changes in cell state that can serve as the initiator of disease.
Lyme Disease: We are investigating heterogeneity of the immune response during Lyme Disease caused by the spirochaete Borrelia. An outstanding question in the field is why some patients resolve disease with antibiotic therapy while others progress to post-treatment disease. Using systems biology approaches we are dissecting the mechanisms of pathogen clearance and deriving immune correlates of disease.
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