Influence of reactive oxygen intermediates in the control of African trypanosomiasis in mice

African trypanosomes are parasitic protozoa that cause fatal disease in humans and domestic livestock. Though domestic animals are susceptible to trypanosomiasis, certain wild animals have developed resistance mechanisms. The African cape buffalo can control the early stages of trypanosome infection by increasing plasm and erythrocyte levels of the reactive oxygen intermediate (ROI), hydrogen peroxide (H2O2). Cape buffalo are able to increase the amount of H2O2 produced by the purine catabolic enzyme xanthine oxidase by supplying more substrate in the blood microenvironment and by decreasing the plasma, and erythrocyte levels of catalase, a H2O2 degrading enzyme. My work has been to attempt to manipulate the ROI generating capabilities of mice to recreate this defense mechanism in a small laboratory animal model. Initial experiments revealed that Balb/c, C57Bl/6 and C3H/HeOu mice have all the purine catabolic enzymes necessary to generate trypanocidal amounts of H2O2. However, unlike the buffalo, all of these mouse strains are susceptible to infection by trypanosomes and their serum is not trypanocidal in vitro. Therefore, the ROI generating capabilities of Balb/c, gamma-interferon knockout Balb/c mice and OH catalase-reduced mutant mice were altered by feeding additives, either in a pellet or liquid diet base, to the mice to either inhibit or enhance ROI generation. Only one combination resulted in a slight but significant decrease in parasitemia: C3H catalase-reduced mice fed the catalase inhibitor 3-amino-triazole. Though parasitemia was not effected in any of the other mouse/diet combinations, the mice were effected in some experiments. Gamma-interferon knockout male mice died significantly earlier than female mice, with or without ROI alterations. Mice maintained on a liquid diet had a significantly reduced acceleration of trypanosome-induced inflammation, but this effect was abrogated when the glutathione precursor N-acetyl-cysteine was included in the diet. This indicates that the diets do have an effect on ROI generation in mice, though parasitemia remained largely unaffected. Thus trypanosomes are able to avoid or neutralize ROI in mice. However, they are susceptible to similar ROI levels in buffalo, suggesting a component in the mice that the trypanosomes are able to utilize to inhibit ROI-induced damage