Entamoeba histolytica is the third leading cause of death from parasitic disease, yet the factors which determine the ability of a strain to cause invasive amebiasis are poorly understood. Studies focused on the differences between the interactions with the intestinal mucosal of potentially invasive E. histolytica and the commensal protozoan, E. dispar, should provide important insights into basic host defenses in the bowel. For successful invasion. E. histolytica trophozoites must circumvent a number of immune and non-immune host defenses against sIgA and the microbicidal activity of activated neutrophils and their oxidative products. We will evaluate the interactions of E. histolytica and E. dispar with host mucosal defenses by:
Aim 1. Evaluate the role of sIgA in protection against amebic infection by evaluating the effect of immune sIgA on trophozoite binding and on the induction of an inflammatory cytokine response, cleavage of sIgA by the E. histolytica cysteine proteinase, and the effect of specific sIgA on invasion in human intestinal xenografts.
Aim 2. Compare the susceptibility of E. histolytica and E. dispar to oxidative attack by testing the ability of neutrophils and their oxidative products to kill E. histolytica and E. dispar, comparing the antioxidant activity of E. histolytica, E. dispar and G. lamblia, determining the ability of sIgA or IgG to block antioxidant activity, and evaluating the regulation of the antioxidant gene.
Aim 3. Evaluate the effect of blocking antioxidant activity on amebic invasion by ablating expression of the 29 kD antioxidant and superoxide dismutase in E. histolytica by antisense RNAs, transfecting E. dispar with the antioxidant gene for E. histolytica, and testing the importance of antioxidant activity on invasion of human intestinal xenografts. By providing important new insights into parasite and host factors which determine the outcome of infection invade with E. histolytica and E. dispar, these studies will increase our knowledge of the basic host defenses in the bowel.
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