| Entamoeba histolytica, the causative agent of amebic colitis and amebic liver abscess, kills thousands of people annually worldwide. This protozoan parasite is able to kill host cells by lysing them as well as by inducing them to undergo programmed cell death by a caspase-dependent process. This thesis examines the mechanism by which E. histolytica induces apoptosis in host hepatocytes during liver infection.; The first study presented is a transcriptional analysis of a mouse model of amebic liver abscess to determine which host factors are up regulated in response to amebic infection. Based on these studies, death receptor pathway effectors as well as the mitochondrial pathway of apoptosis are likely involved in the programmed cell death of hepatocytes in amebic liver abscess.; Based on the transcriptional analysis, the second study presents data from mouse model experiments designed to test the importance of particular effectors, namely Bim, Bid, Fas, and TNFR, for hepatocyte apoptosis in E. histolytica infected livers. Results suggest that Bim and Bid are not important in amebic liver abscess and also that the Fas and TNFalpha-dependent pathways can be simultaneously disrupted without significantly affecting amebic liver abscess.; The third study examines the role in host cell apoptosis of two amebic proteins, amoebapore-A and cysteine protease 5, that are known to be important for E. histolytica virulence. For these studies, an in vitro flow cytometry assay was developed using E. histolytica strains deficient in either amoebapore-A or cysteine protease 5 and HepG2 human hepatocellular carcinoma cells. These studies suggest that neither of these amebic proteins is required to induce apoptosis in the host hepatocytes.; These studies suggest that the mechanism of E. histolytica-induced hepatocyte apoptosis may occur via a unique combination of known mechanisms or via a completely new mechanism. |
