Question

The reason why trypanosomes like Trypanosoma brucei are successful invading into the bloodstream is due to antigenic variation of a homogeneous Variant Surface Glycoprotein (VSG) coat. However, to accomplish this, the trypanosome VSG gene in the active expression site is degraded and replaced with the donor VSG gene. Explain why there is not an eventual loss of these VSG genes in the trypanosome genome over time.

Answer 1

Only one VSG is expressed by a trypanosomeat a time; trypanosomes expressing the same VSG are said to belong to the same variable antigenic type (VAT). In the blood of a chronically infected mammal, there is a hierarchical expression of VATs with some always being detected early in infection and others later. Protective immune responses of the host are VAT-specific and parasites expressing these VATs are cleared from the blood (through complement-mediated lysis and/or opsonization) and the parasitemiadeclines. Remission is invariably followed by recrudescence, however, as trypanosomes expressing other VATs multiply. Thus, the numbers of trypanosomes detectable in the blood fluctuate wildly such that the infection characteristically consists of a series of parasitaemic peaks.
Switching from one VAT to another occurs spontaneously; it is not induced by the host's immune response as it occurs in in vitrocultures of bloodstream stage trypanosomes. The rate of switching varies between 10−2 and 10−7 switches per cell generation and is higher in tsetse-transmitted than in syringe-passaged infections. Each VSG is encoded by a separate VSG gene and switching involves the expression of a different VSG gene at one of a few mutually exclusive chromosomal telomeric expression sites. These are two principal mechanisms by which a VSG gene can be expressed: It can be activated in situ or a copy (the so called expression-linked copy or ELC) of a chromosomal internal gene (basic copy) may be inserted at a telomeric expression site, displacing the previously expressed gene. What controls the rate of switching or the order in which heterotypes grow up to become homotypes is not known.

Trypanosoma brucei appears to have about 1000 VSG genes underlying its VAT repertoire though T. b. gambiense and T. vivax may have a smaller number. Late in an infection new chimeric VSG genes may arise as a result of only partial replacement of the outgoing gene at the expression site by the incoming expression-linked copy. For a given trypanosome species or subspecies, a number of VAT repertoires (serodemes) can be discerned in different or in the same geographical areas. Despite the high immunogenicity of VSGs, the prospect of vaccinating potential hosts against all VATs in all serodemes is clearly hopeless. A more promising approach was thought to be to protect such hosts against tsetse-transmitted trypanosomiasis by rendering them solidly immune to the metacyclic VATs (M-VATs) that constitute a limited subset of the bloodstream repertoire (12 in T. congolense, ≤ 27 in T. brucei). Metacyclic VSG genes always reside at the telomeres of large chromosomes, are activated in situ and can be expressed at a lower temperature than bloodstream form VSGs. T. brucei has over 120 chromosomes, about 100 of which are ‘minichromosomes’ (average size 100 kb as compared with >1 Mb large chromosomes); the minichromosomesappear to house only VSG genes.

Although immunity against infection with metacyclic trypanosomes can be induced by allowing cattle to become infected by fly bites and then treating the resulting infection as soon as the parasitemia becomes patent, such immunity is usually short-lived. Breakthroughs in infection can occur as a result of replacement of a metacyclic VSG (M-VSG) gene with a bloodstream stage VSG as part of the process of antigenic switching occurring at a M-VSG gene expression site. The ability of the M-VAT repertoire of a given serodeme to evolve in this way ensures that hosts in a given area do not all become immune to a given serodeme. With the collapse of plans for vaccination based on M-VATs, attention has turned to the possibility of vaccination against nonvariable antigens of the parasite, that is those common to all trypanosomes irrespective of their VAT. Such common antigens are largely unexposed and so unable to react with host effector mechanisms, but the discovery that the trypanosome relies on receptor-mediated endocytosis to take up certain necessary host proteins (e.g. transferrin, low-density lipoprotein) from its flagellar pocket has raised hopes that the blocking of exposed receptors by host antibodies might halt or slow the infection. Alternatively, transmission blocking antibodies raised to procyclin or some other component of the trypanosome surface in early vector development might be used to limit the spread of trypanosomiasis by tsetseflies.