Interferons (IFNs) represent a group of cytokines that are best characterized for their ability to “interfere” with viral infection, but are also appreciated for their antiproliferative (antitumor) effects and their immunemodulatory properties. Consequently, interferons are used in clinical settings for the treatment of viral infections (e.g. Hepatitis C), malignancies (e.g. melanoma) and autoimmune disorders (e.g. Multiple Sclerosis).
Our goal is to understand the mechanisms by which interferonsmediate these pleiotropic effects on a cellular and molecular level by investigating the following areas:
1) Characterization of the signal transduction mechanisms that permit IFNs to activate the transcription of defined cellular genes: Formation of DNA-binding complexes comprised of tyrosine phosphorylated STAT transcription factors involves the activation of members of the JAK family of tyrosine kinases. However, additional post-translational events ( e.g. modification through ubiquitin-like molecules, protein methylation, etc.) exert control over activation of STAT proteins, in addition, not all biological effects of IFNs are exclusively mediated by the JAK/STAT pathway.
2) Define the cellular and molecular events that govern the immunemodulatory properties of interferons: We have identified an important novel function of type I interferons and STAT1 in the positive and negative selection of T cells during thymic development, as well as T cell activation. Our findings are likely to be of great significance as a link between viral infections and the development of autoimmune diseases, and furthermore have direct implications on the efficacy of interferons in the treatment of immune disorders.
3) Elucidate the pathways by which the immune system recognizes bacterial or viral infection and initiates an innate immune response: The induction of type I interferons is one of the earliest innate immune responses to viral as well as bacterial pathogens. We had previously discovered that Toll-like receptors (TLRs) activate the transcription factor IRF3, which is essential for the production of interferons as well as other pro-inflammatory cytokines after pathogen recognition. We are interested in the signaling mechanisms that lead to IRF3 activation, and how invading pathogens (e.g. Hepatitis C virus, B. anthracis) can interfere with these pathways and consequently paralyze the host’s innate immune response?
Tanabe Y, Nishibori T, Su L, Arduini RM, Baker DP, David M. (2005). Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-alpha beta responses in T lymphocytes. J. Immunol. 174(2):609-613.
Nishibori T, Tanabe Y, Su L, David M. (2004). Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J. Exp. Med. 199(1):25-34.
Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschman HR, David M. (2001). Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Cell 104(5):731-734.
Navarro L, David M. (1999). p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J. Biol. Chem. 274(50):35535-35538.
Dang O, Navarro L, Anderson K, David M. (2004). Cutting edge: anthrax lethal toxin inhibits activation of IFN-regulatory factor 3 by lipopolysaccharide. J. Immunol. 172(2):747-751.
Chiang E, Dang O, Anderson K, Matsuzawa A, Ichijo H, David M. (2006). Cutting edge: apoptosis-regulating signal kinase 1 is required for reactive oxygen species-mediated activation of IFN regulatory factor 3 by lipopolysaccharide. J. Immunol. 176(10):5720-5724.
Michael David received his Ph.D in Pharmacology from the University of Vienna, Austria and did his postdoctoral research at the Center of Biologics Evaluation and Research in Bethesda, Maryland. He was an Erwin-Schroedinger and a Fogarty Fellow, and received Scholar Awards from the Sidney Kimmel Cancer Foundation and the National Multiple Sclerosis Society.