The immune system has evolved complex mechanisms to keep us safe from viruses, bacteria, parasites and other deadly threats that exist in the environment. However, the immune system is a double-edged sword; it is absolutely required for defense against infection, but when dysregulated, it can cause severe damage to the body. As it is difficult to tackle this complexity using traditional scientific approaches alone, the Aderem Lab employs the tools of systems biology to develop a more complete picture of how our cells detect and respond to infectious agents. Our research focus is the innate immune system, the body’s first line of defense. Innate immune cells “sense” invading microbes and then program adaptive responses, which are critical to establishing long-term protective immunity. Scientists in the Aderem Lab are studying innate responses to HIV, tuberculosis, influenza and other pathogens that significantly impact global health. Our goal is to define the mechanisms that result in a successful immune response to infection or vaccination and identify targets for therapeutic intervention to correct inadequate or dysregulated responses. By integrating systems biology-based “omics” approaches (genomics, transcriptomics, proteomics, metabolomics, etc.), we aim to develop predictive models of the complex interactions that maintain the fine balance between host defense and inflammatory disease.
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.
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 Global Infectious Disease Research, including the Zak, Sherman, and Urdahl Labs, as well as the Baliga Lab at the Institute for Systems Biology.
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.
In the News
CGIDR Researchers Awarded $17.2 Million Tuberculosis Grant from NIH
Researchers from the Center for Global Infectious Disease Research (CGIDR) have been awarded a grant from the National Institute of Allergy and Infectious Diseases, one of the U.S. National Institutes of Health, to take a systems-level approach to the critical problem of tuberculosis (TB) infection, specifically focusing on the progression from infection to disease, and variability of treatment. The research ultimately seeks to catalyze new, transformative interventions, such as diagnostics, drugs and vaccines.
About Dr. Alan Aderem
Alan Aderem, PhD, is a biologist, specializing in immunology and cell biology, with emphasis on the innate immune system, generally regarded as the body’s first line of defense to any pathogen. Aderem co-founded the Institute for Systems Biology (ISB) with Leroy Hood and Ruedi Aebersold in 2000 and served as its director until 2011.
A native of South Africa, Aderem obtained his PhD at the University of Cape Town and completed a postdoctoral fellowship at the Rockefeller University in New York in the laboratory of Dr. Zanvil Cohn. He rose through the ranks at the Rockefeller University, becoming head of the Laboratory of Signal Transduction in 1991. In 1996, he accepted a professorship of immunology and medicine at the University of Washington in Seattle. In his free time, he enjoys sailing.
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