Research Interests
Intracellular signaling mechanisms that regulate macrophage innate immune responses with an emphasis on response to IgG immune-complexes (IC) and bacterial ligands.
Project 1: Macrophage Fc Receptor function.
One major goal of the lab is to understand the regulation of expression and function of IgG receptors (Fc?R) in monocytes and macrophages. Fc?R bind to and clear IgG ICs by a process termed phagocytosis. The phagocytic process is often accompanied by the generation of inflammatory cytokines and reactive oxygen and nitrogen radicals, which results in tissue damage. Therefore, phagocytosis must be tightly regulated.
Recent work from our laboratory and others established that the phagocytic process is subject to multiple regulatory mechanisms. One level of regulation occurs by the modulation of the ratio of activating to inhibitng Fc?R on monocytes and macrophages. A second level of regulation is mediated by intracellular phosphatases (inositol phosphatases, protein tyrosine phosphatases). Ongoing research in the laboratory is aimed at understanding the molecular details of these regulatory mechanisms.
An understanding of Fc?R function is critical since these receptors are not only involved in IC-mediated inflammation, but also serve a critical role in antibody-based therapeutic approaches for deseases such as cancer.
Project 2: Mechanisms of macrophage response to Francisella infection
Francisella tularensis primarily infects monocytes and macrophages and causes the disease Tularemia. Molecular details of host cell responses to infection are poorly characterized. Francisella infection of macrophages results in the induction of inflammatory cytokines. The goal of this project is to unravel the biochemical pathways activated by Francisella infection of macrophages, and the regulatory mechanisms that are in place to maintain homeostasis. We use multiple approaches, including microarray analyses, biochemical, signal transduction and molecular biology approaches to gain an understanding of host responses. We anticipate that once molecular mechanisms of host response are defined one can devise therapeutic approaches to boost host resistance to infection.
Recent Publications
Butchar, J.P., Rajaram, M.V.S., Ganesan, L.P., Parsa, K.V.L., Clay, C.D., Schlesinger, L.S. and S. Tridandapani. (2007) Francisella tularensis induces interleukin-23 production in human monocytes. J. Immunol. 178(7):4445-54.
Rajaram, M.V.S., Ganesan, L.P., Parsa, K.V.L., Butchar, J.P., Gunn, J.S., and S. Tridandapani (2006) Akt/PKB modulates macrophage inflammatory response to Fransicella infection and confers a survival advantage in mice. J. Immunol. 177(9):6317-24
Parsa, K.V.L., Ganesan, L.P., Rajaram, M.V.S., Gavrilin, M. A., Balagopal, A., Mohapatra, N., Wewers, M.D., Gunn, J.S., and S. Tridandapani (2006). Macrophage pro-inflammatory response to Francisella novicida infection is regulated by the SH2 domain-containing inositol phosphatase SHIP. PLoS Pathogens 2(7):e71
Ganesan, L.P., Joshi, T., Fang, H., Kutala, V.K., Roda, J., Trotta, R., Lehman, A., Kuppusamy, P., Byrd, J.C., Carson, W.E., Caligiuri, M.A.and S. Tridandapani. (2006) Fc?R-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways. Blood. 108(2):718-25
Ai, J., Maturu, A., Johnson, W., Wang, Y., Marsh, C.B. and S. Tridandapani (2006) SHIP-2 regulates Fc?R-mediated phagocytosis in murine macrophages independently of SHIP-1. Blood 107(2):813-20. Epub 2005 Sep 22.
Lab members:
Jonathan P. Butchar, PhD (Postdoc)
Murugesan Rajaram, PhD (Postdoc)
Anne-Sophie Wavreille, PhD (Postdoc)
Kishore Parsa (Grad. Student)
Payal Mehta (Grad. Student)
Donna Cain (Research Assistant)
