Serum Xanthine Oxidase: Origin, Regulation, and Contribution to Control of Trypanosome Parasitemia

Abstract

African trypanosomiasis is caused by Salivarian trypanosomes, tsetse fly-transmitted protozoa that inhabit the blood plasma, lymph and interstitial fluids, and, in the case of Trypanosoma brucei species, also the cerebrospinal fluid of mammal hosts. Trypanosomiasis in people and domestic animals manifests as recurring waves of parasites in the blood and is typically fatal. In contrast, trypanosomiasis in Cape buffaloes, which are naturally selected to resist the disease, is characterized by the development of only one or a few waves of parasitemia, after which the infection becomes cryptic, being maintained by the presence of 1-20 mammal-infective organisms/ml of blood. The control of the acute phase of parasitemia in Cape buffaloes correlates with a decline in blood catalase activity and the generation of trypanocidal H(2)O(2) in serum during the catabolism of endogenous purine by xanthine oxidase. Here we review features of this response, and of trypanosome metabolism, that facilitate H(2)O(2)-mediated killing of the parasites with minimal damage to the host. We also discuss the origin and regulation of serum xanthine oxidase and catalase, and show how recovery of serum catalase in infected Cape buffaloes precludes a role for H(2)O(2) in the long-term, stable suppression of trypanosome parasitemia.

Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification

“…Urate also protects protein from nitration; it can chelate metal ions, such as copper and iron, and prevent them from participating in redox cycling. The degradation product of urate, allantoin, was found in vivo, supporting claims that urate indeed is an ef cient in vivo antioxidant (9,21,262).…”

Clinical Chemistry of Congenic Mice with Quantitative Trait Loci for Predicted Responses to Trypanosoma congolense Infection

“…Uric acid is an intermediate in purine catabolism, and levels can be increased as a consequence of infections and massive cell death. Uric acid metabolism has been implicated in the control of malaria and also T. congolense infection in cape buffalo (6,34). However, in the present study uric acid levels remained reasonably constant during the course of infection in A/J and BALB/c mice, while they fluctuated between 2 and 4 mg/dl in C57BL/6 mice (not shown).…”

Role of Xanthine Oxidoreductase as an Antimicrobial Agent

“…Because such XOR is largely in the XO form, as a result of proteolysis (39), it tempting to see the circulating enzyme as a systemic source of antimicrobial ROS. Perhaps the most convincing example of such a role is found in Cape buffaloes, in which a natural resistance to trypanosome parasitemia has been attributed to hydrogen peroxide derived from serum XO (68). In general, however, the situation is far from clear.…”

“…It has the capacity to bind to glycosylaminoglycans on the surface of vascular endothelial cells (2,53) and, thus concentrated, to initiate oxidative damage in distal organs (69). In this context, it is of interest that anti-XOR antibodies are also present in mammalian serum (68). In fact, the levels can be remarkably high, accounting for as much as 6% of the total immunoglobulin M antibodies in healthy human subjects (6).…”