Systems Approach to Immunity and Inflammation
Systems approaches combine what we already know (prior biological knowledge) with the analysis of massive amounts of new data (collected through global measurement technologies and computational methods). Merging these levels of information can reveal novel regulatory interactions between molecules and places them in context within the immune system. Identifying regulatory nodes in immune cells that control specific sub-networks of the innate response is critical to the development of therapeutic strategies that aim to either harness specific immune functions, such as for vaccine adjuvants, or to mitigate inflammation-driven diseases such as atherosclerosis and lupus. Two key cell types in the innate immune system are macrophages and dendritic cells, which display an arsenal of receptors for detecting pathogens and play critical roles in pathogen clearance, cytokine production, and the initiation of adaptive immunity. Systems biology studies of macrophages and dendritic cells in the Aderem Lab have generated testable hypotheses for the role of a large number of molecules in innate immune responses. We are testing how mutating these molecules or perturbing their networks will impact immune responses against tuberculosis, HIV, influenza, and other pathogens. To learn more, please visit www.SystemsImmunity.org.
Omics for TB Disease Progression (OTB)
Roughly one third of the world’s population is latently infected with Mycobacterium tuberculosis. Over their lifetimes, many of these individuals (with no outward signs of illness) will transition to active disease. We have no biological understanding of what drives this conversion from latent to active disease states. The overall goal of this project is to apply omics technologies and systems-based modeling to define the key bacterial and host determinants of the progression from latent infection to active disease. This work involves collaborations with several groups at the Center for Infectious Disease Research, including the Zak, Sherman, and Urdahl Labs, as well as the Baliga Lab at the Institute for Systems Biology (www.omics4tb.org).
Exploring Innate Immune Signaling
The innate immune system detects pathogens and pathogen components such as lipopolysaccharide (LPS) via pattern recognition receptors. These include the Toll-like receptors (TLRs), the Nod-like receptors (NLRs), the Rig-I-like receptors (RLRs), cytoplasmic DNA receptors (cGAS), and others. Some of these receptors trigger anti-viral responses by inducing type I interferons (type I IFNs). This induction must be tightly regulated since over-exuberant production of IFN can contribute to autoimmunity. The transcription factor IRF7 is a “master regulator” of systemic type I IFN responses. While much is known about the activation of IRF7, the mechanisms by which it is regulated and de-activated remain poorly explored. We have recently identified a regulatory circuit involving IRF7 and another transcription factor, FOXO3, whereby excessive IFN responses are kept in check by FOXO3-mediated repression of IRF7-dependent genes (Litvak et al., Nature 2012). We are currently extending these studies to explore the regulation of other signaling networks that are engaged downstream of TLRs, RLRs, and other receptors. This is an exciting area of research that underscores the importance of genetic and epigenetic regulation of interferon and illuminates new concepts in innate immunity.