CRITICAL ROLE OF THE ASC/CASPASE-1 PATHWAY IN TICK-BORNE RICKETTSIOSES

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DESCRIPTION (provided by applicant): This proposal describes a three year supervised career development program in Public Health research. Joap Pedra, Ph.D. completed his doctoral program in Medical Entomology at Purdue University and is currently a "Brown-Coxe Fellow of Medicine" at Yale University expanding his scientific skills in the field of immunobiology. Dr. Pedra is committed towards becoming an independent investigator in the field of tick-borne rickettsioses. Tick-borne rickettsioses are directly relevant to the health protection goals defined by the Centers for Disease Control and Prevention. Tick-borne rickettsial pathogens not only have the potential to affect the health of all segments of the population, but also can be used as biological weapons in case of a terrorist attack. Dr. Fikrig will mentor the scientific development of Dr. Pedra. Dr. Fikrig is a Professor of Medicine, Microbial Pathogenesis and Public Health at Yale University and a recognized leader in the field of tick-borne diseases. The research will focus on the mechanisms of immunity against Anaplasma phagocytophilum and Rickettsia conorii, two pathogens from the tick-borne rickettsial group. The mechanisms of immunity against A. phagocytophilum and R. conorii are largely unknown. Preliminary results shown by Dr. Pedra have demonstrated that Nod-like receptors play a critical role against A. phagocytophilum infection. Nod-like receptors recognize intracellular pathogens and trigger the cytokines IL-1b and IL-18 through their effect on the protease caspase-1. The research proposal described in this application aims to (1) examine the exact mechanism that triggers caspase-1 activation upon A. phagocytophilum infection; (2) assess the role of caspase-1/IL-18 in the adaptive immune response against A. phagocytophilum; and (3) identify the Nod-like receptor that triggers caspase-1 activation upon R. conorii infection. To accomplish these goals, Dr. Pedra will have free access to the modern facilities present at Yale University and will make use of the most current techniques available in immunobiology, microbial pathogenesis and proteomics.