With over 40% of the world's population at risk from diseases such as malaria, parasitic disease represents an ever-increasing global health burden. Inherent in any parasitic relationship is the ability of the pathogen to stave off attack by the host's immune system. While considerable attention has been paid to paradigms for parasitic evasion of antibody or T-cell mediated immunity by pathogens, new paradigms have begun to emerge that highlight a parasite's ability to evade and modulate the innate immune system. From these studies, it is clear that active immunosuppression may play an important role in achieving successful parasitism. Phagocytosis of released hemozoin has been shown to disrupt oxidative burst within macrophage and preclude subsequent phagocytosis. Further, in this macrophage, the key regulatory signals transduction enzyme, Protein Kinase C (PKC) has been shown to be modified by the highly reactive electrophile 4-hydroxynonenal (HNE). We hypothesize that the hemozoin-mediated peroxidation of arachidonic acid results in the production of HNE that in turn covalently inactivates PKC by forming adducts to key residues. To understand how this seemingly insignificant by-product of parasitic hemoglobin metabolism is capable of disrupting NADPH oxidase assembly it is proposed to: (1) Demonstrate that in vitro hemozoin is a reactive reagent for the formation of 4-hydroxynonenal (HNE). (2) Map the loci of HNE adduction on Protein Kinase C (PKC) by applying emerging mass spectrometric methods. (3) Probe HNE adduction sites on PKC in hemozoin challenged macrophages. The successful completion of this grant will establish the molecular basis of hemozoin mediated inactivation of Protein Kinase C and pave the way for more detailed proteomic analysis of HNE adducts within macrophages.
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