Amebic colitis and liver abscess are due to infection with the enteric protozoan parasite Entamoeba histolytica. The World Health Organization estimates that approximately 50 million people worldwide suffer from invasive amebic infection each year. The adherence of E. histolytica trophozoites to intestinal mucins and epithelial cells by a galactose-binding (Gal/GalNAc) lectin is necessary for the parasite to kill host cells and invade. We have discovered that the intermediate subunit of this lectin is part of an E. histolytica gene family of more than 80 transmembrane kinases (TMK). The TMK kinase domains are novel and the number of TMKs is unprecedented in a unicellular organism. We hypothesize that the TMKs are a major receptor system for sensing the environment and controlling the invasive behavior of the parasite. We propose to test if the TMKs undergo antigenic variation, determine if TMK 96 is a dual specificity (tyr and ser/thr) kinase and identify its downstream effectors and regulators, and study the biologic activities regulated by TMK 96. We will focus on the role of TMK 96 in the adherence, killing and endocytosis of apoptotic corpses as it has been identified as part the phagosome proteome. Successful completion of these studies will provide fundamental knowledge of these novel receptor kinases and insight into the means by which the parasite controls its invasion into the human intestine.
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