The Rate of Proliferation among African Trypanosomes is a Stable Trait that is Directly Related to Virulence

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Abstract
The relationship between the growth rate of Trypanosoma brucei gambiense and its virulence was investigated. A cloned, monomorphic, slow growing, and relatively avirulent line of T. b. gambiense was serially passaged at 3- to 5-day intervals through immunosuppressed mice. The growth rate measured within the first 2 patent days of infection did not vary significantly through the first 25 passages but by passage 50 had decreased significantly from 11.9 ± 1.1 hr to 9.0 ± 0.7 hr. A clone from passage 50 and three different second peak heterologous variants all had statistically similar growth rates, indicating that the rate of proliferation was a stable trait. With the faster rate of proliferation there was a corresponding increase in virulence. The inoculum necessary to kill 50% of normal outbred mice in the first peak of parasitemia (LD50) dropped significantly from 3 × 106 first passage parasites to 4 × 105 passage 50 parasites. The lethal load for both fast and slow growing organisms was the same (> 2 × 109 trypanosomes/ml of blood). To further link virulence and growth rate, a strong correlation (r = 0.89) was measured when generation times of 10 closely related lines of T. b. gambiense, and 2 lines of pleomorphic T. b. rhodesiense were compared to their LD50 values. While the rate of trypanosomal proliferation was similar between the day of inoculation through the second patent day, it slowed to 64% of that level once parasitemias exceeded 3 × 108 organisms/ml of host blood. This inhibition of growth occurred to similar degrees in both monomorphic and pleomorphic lines of trypanosomes, at about the same level of parasitemia, in both immunosuppressed or immunologically intact mice. Virulence could not be correlated to the growth rate measured late in the first peak of parasitemia, a pleomorphism of the trypanosomal line, or its variant antigen type.