The innate immune response is an ancient form of host defense against infection, trauma, and other injury. Many elements of innate immunity are conserved in organisms, ranging from tomatoes to Drosophila melanogaster to human beings. We study the role of the Toll/IL-1 intracellular signaling pathway in both the afferent and effector arms of the innate immune response in humans and mice. The proteins MyD88, members of the interleukin-1 receptor associated kinase (IRAK) family, and TRAF6 make up this signaling cassette. They transduce signals from the Toll-like receptors in the afferent limb of the innate response (such as those triggered by Gram-negative and Gram-positive bacteria, LPS, peptidoglycan, lipotechoic acid, and heat shock proteins) and the IL-1 and IL-18 receptors in the efferent arm, and then distribute the signal to several downstream signaling cascades, including those activating NF-kB, the stress activated protein kinases, and p38a.
Thus the Toll/IL-1 signaling module both senses injury and mounts the proinflammatory response to limit it.
We have genetically inactivated IRAK in mice and are characterizing the defects in host responses to numerous pathogens at the biochemical, cellular, and in vivo levels. We have found that IRAK-deficient mice and cell lines exhibit impaired intracellular signaling to LPS, IL-1, and IL-18. These derangements in signaling are tied to altered host defenses. We are currently examining the contributions of two additional IRAK family members, IRAK2 and IRAK-M, to signal transduction through this pathway. We have also uncovered a critical role for this pathway in a tissue not traditionally considered part of the immune system the myocardium. Results from these studies may lead to antiinflammatory therapy for children with severe infections, and may reverse or prevent the cardiovascular manifestations that characterize clinical septic shock.
RESEARCH INTERESTS
Innate Immune Response to Infection
Innate Immune Signaling and Autoimmunity
Innate Immunity and Myocardial Dysfunction
RECENT PUBLICATIONS
Binck, BW, MF Tsen, M Islas, DJ White, R Schultz, M Willis, V Garcia, JW Horton, JA Thomas, "Bone marrow derived cells contribute to contractile dysfunction in endotoxic shock" The American Journal of Physiology: Heart and Circulatory Physiolog, 288(1)::H577-583, January 2005
Verdrengh, M, JA Thomas, O Hultgren, "IL-1 Receptor-Associated Kinase 1 mediates protection to Staphylococcus aureus infection" Microbes and Infection, 2004, 6(14):.:1268-72., 2004
Li, T, J Hu, JA Thomas, L Li,, "Differential induction of apoptosis by LPS and Taxol in monocytic cells" Molecular Immunology, December 2004
Horton, JW, J Tan, D. J White, DL Maass, and JA Thomas,, "Selective decontamination of the digestive tact attenuated the myocardial inflammation and dysfunction that occur with burn injury" The American Journal of Physiology: Heart and Circulator, 287:H2241-H2251, July 2004
White, J, JA Thomas, DL Maass, JW Horton, "The cardiac effects of burn trauma complicated by aspiration-pneumonia-induced sepsis" The American Journal of Physiology: Heart and Circulatory Physiology, 825(1)::H47-58., 2003
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