Two species of African trypanosomes, which are flagellated protozoans, can cause sleeping sickness, a chronic, debilitating disease transmitted to humans and cattle by the bite of the tsetse fly. In the bloodstream, a trypanosome differentiates into a long, slender form that continues to divide every 4-6 h. The disease progresses through several stages, beginning with an early (systemic) stage in which trypanosomes multiply in the blood and progressing to a neurologic stage in which the
Antibodies to variant 3
Antibodies to variant 2
Antibodies to variant 1
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Approximate time after tsetse fly bite, weeks
Duplication and translocation to expression site
(a) Successive waves of parasitemia after infection with Trypanosoma result from antigenic shifts in the parasite's variant surface glycoprotein (VSG). Each variant that arises is unaffected by the humoral antibodies induced by the previous variant. (b) Anti genic shifts in trypanosomes occur by the duplication of gene segments encoding variant VSG molecules and their translocation to an expression site located close to the telomere. [Part (a) adapted from J. Donelson, 1988, The Biology of Parasitism, Alan R. Liss.]
parasite infects the central nervous system, causing menin-goencephalitis and eventually the loss of consciousness.
As parasite numbers increase after infection, an effective humoral antibody response develops to the glycoprotein coat, called variant surface glycoprotein (VSG), that covers the trypanosomal surface (Figure 17-12). These antibodies eliminate most of the parasites from the bloodstream, both by complement-mediated lysis and by opsonization and subsequent phagocytosis. However, about 1% of the organisms, which bear an antigenically different VSG, escape the initial antibody response. These surviving organisms now begin to proliferate in the bloodstream, and a new wave of parasitemia is observed. The successive waves of parasitemia reflect a unique mechanism of antigenic shift by which the trypanosomes can evade the immune response to their gly-coprotein antigens. This process is so effective that each new variant that arises in the course of a single infection is able to escape the humoral antibodies generated in response to the preceding variant, so that waves of parasitemia recur (Figure 17-12a).
Several unusual genetic processes generate the extensive variation in trypanosomal VSG that enables the organism to escape immunologic clearance. An individual trypanosome carries a large repertoire of VSG genes, each encoding a different VSG primary sequence. Trypanosoma brucei, for example, contains more than 1000 VSG genes in its genome, clustered at multiple chromosomal sites. A trypanosome expresses only a single VSG gene at a time. Activation of a VSG gene results in duplication of the gene and its transposition to a transcriptionally active expression site (ES) at the telomeric end of specific chromosomes (Figure 17-12b). Activation of a new VSG gene displaces the previous gene from the telomeric expression site. A number of chromosomes in the trypanosome have transcriptionally active expression sites at the telomeric ends, so that a number of VSG genes can potentially be expressed, but unknown control mechanisms limit expression to a single VSG expression site at a time.
There appears to be some order in the VSG variation during infection. Each new variant arises not by clonal outgrowth from a single variant cell but instead from the growth of multiple cells that have activated the same VSG gene in the current wave of parasite growth. It is not known how this process is regulated among individual trypanosomes. The continual shifts in epitopes displayed by the VSG make the development of a vaccine for African sleeping sickness extremely difficult.
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