Trypanosoma lewisi Infection in the Rat: Effect of Adenine

Abstract

The reproductive activity of Trypanosoma lewisi was strikingly enhanced and sometimes prolonged for 2 days when sublethal doses of adenine were given to rats. The drug was effective when given for 5 or 7 days in the diet and/or intraperitoneally, starting one or two days before infection through two days after infection. Peak parasitemia was also enhanced. In terms of host immunity, daily sublethal doses of adenine given to rats within two days before or after infection with T. lewisi significantly depressed a hitherto unrevealed natural immunity to reproduction of the trypanosomes, but only slightly modified the development of acquired immunity.Ablastin is an antibody elaborated by the rat that inhibits reproduction of its blood parasite, Trypanosoma lewis'i (1). Ablastin, in addition, decreases carbohydrate metabolism of the trypanosomes (2), protein and nucleic acid synthesis (3), and some enzymes (4). At peak parasitemia, an early trypanolysin sweeps many of the trypanosomes from the blood, and a later one ends the infection (5, 6). Sublethal doses of adenine (oral or parenteral) produce toxic effects in dogs, mice, and rats such as renal damage (7-10) and possible derangements of nucleic acid metabolism (7). Adenine also inhibits growth of mammalian cells in vitro at concentrations of 10-' M or higher (11). In view of these effects, excess adenine might be assumed to interfere with the product ion of antibodies by inhibiting DNA synthesis in rapidly proliferating antibody-forming cells. Thus, flooding the rat with adenine before the start of ablastin formation might inhibit synthesis of ablastin so that T. lewisi, when introduced into the rat, would divide more prolifically. Flooding the rat with adenine after ablastin is formed might decrease further formation of ablastin to such an extent that T. leuisi, already introduced into the rat and partially inhibited from dividing, would resume reproduction. The first of these situations, but not the second one, was encountered in the current work. In addition, adenine, when introduced early in the infection, delayed the appearance of the early trypanolysin. MATERIALS AND METHODSThe strain of white rats, designated SD/Anl [Anl 631, was started from germfree Sprague-Dawley weanling rats that were purchased from A. R. Schmidt Co., Inc., Madison, Wis., in 1963. In 1964, the rats suffered a hemorrhagic disease associated with a possible vitamin K deficiency (12), but were healthy and free of respiratory infections and external and internal animal parasites at the time the current experiments were performed in the fall of 1965. Ten series of three female rats were used: each rat weighed 120-230 g when infected intraperitoneally with trypanosome-containing blood from donor infected rats. Series 1 through 7 were given adenine; the 3 control series were not. All rats were housed in air-conditioned rooms at a temperature of 220C, humidity of 40%, and 12-hr changes of light and dark.The strain of T. leuisi is the same one used by Moulder (2) and Taliaferro and Piz...

Trypanosoma brucei adenine-phosphoribosyltransferases mediate adenine salvage and aminopurinol susceptibility but not adenine toxicity

“…We determined the sensitivity of different T. brucei lines to adenine and analogues with an in vitro test using the fluorescent dye AlamarBlue® as an indicator of cell viability ( Räz et al, 1997 ). As observed previously ( Taliaferro and D’Alesandro, 1971; Geiser et al, 2005 ), adenine itself was toxic to trypanosomes with an IC 50 value around 300 μM ( Fig. 5 ); bloodstream-form and procyclic T. brucei were equally sensitive.…”

“…Adenine at high (e.g. millimolar) concentrations is toxic to trypanosomes ( Taliaferro and D’Alesandro, 1971; Geiser et al, 2005 ). Adenine toxicity is a phenomenon also known from Escherichia coli , where it is exacerbated by genetic disruption of hypoxanthine and guanine phosphoribosyltransferases (E.C.…”

The availability of purines influences both the number of parasites and the splenocyte levels of purine-metabolizing enzymes in trypanosome-infected mice

“…report [28], although the conclusions are quite different), it appeared that the magnitude of trypanosome growth in the infected mouse was restricted by the supply of purines. This was indicated by the effects of both adenosine and DCF on the magnitude of trypanosome infection.…”

“…The growth and maintenance of extracellular trypanosomes, such as the rodent and African trypanosomes, is dependent on a supply of purines from their hosts (16,20). It has not been formally proved that the rodent trypanosomes depend on exogenous purines, but it is virtually certain that they do (28), as do many protozoan parasites (17,26,33). The trypanosomes lack the enzymes for de novo synthesis of purines (13)(14)(15)(16)20).…”