"Biting" of human cells by Entamoeba histolytica: a novel cytotoxic mechanism

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I propose to study the pathogenesis of amoebic colitis, a global parasitic infection and a major source of morbidity and mortality of children. Entamoeba histolytica was named "histolytica" for its destruction of host tissues and invasion of the intestine, but the mechanism was unknown. I recently made the surprising discovery that amoebae kill by biting off and ingesting distinct pieces of living human cells, resulting in intracellular calcium elevation and eventual death. I named this "trogocytosis-like ingestion" (Greek, trogo-: nibble) due to similarity to trogocytosis in immune cells. I hypothesize that pathology in amoebic colitis results from parasites invading the intestine by nibbling the epithelial cells that line the gut. It is likely that the novel killing mechanism requires unique phagocytic machinery and that the components represent new drug targets. Therefore, I propose to uncover the signaling mechanisms underlying trogocytosis-like ingestion. Furthermore, I propose to re-examine the long-standing hypothesis that the E. histolytica pore-forming proteins, known as the "amoebapores," are secreted cytotoxic effectors. Successful completion of this work will create a paradigm shift in the function of the amoebapores, and will also allow us to identify novel virulence factors, ultimately allowing us to define the basic mechanism of disease.