Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite

Abstract

African trypanosomes are unicellular, eukaryotic parasites that live extracellularly in a wide range of mammals, including humans. They have a surface coat, composed of variant surface glycoprotein (VSG), which probably is essential and acts as a defence against general innate immunity and against acquired immunity directed at invariant surface antigens. In effect, the VSG is the only antigen that the host can target, and each trypanosome expresses only one VSG. To counter specific antibodies against the VSG, trypanosomes periodically undergo antigenic variation, the change to expression of another VSG. Antigenic variation belongs to the general survival strategy of enhanced phenotypic variation, where a subset of 'contingency' genes of viruses, bacteria and parasites hypermutate, allowing rapid adaptation to hostile or changing environments. A fundamental feature of antigenic variation is its link with the population dynamics of trypanosomes within the single host. Antigenic variants appear hierarchically within the mammalian host, with a mixture of order and randomness. The underlying mechanisms of this are not understood, although differential VSG gene activation may play a prominent part. Trypanosome antigenic variation has evolved a second arm in which the infective metacyclic population in the tsetse fly expresses a defined mixture of VSGs, although again each trypanosome expresses a single VSG. Differential VSG expression enhances transmission to new hosts, in the case of bloodstream trypanosomes by prolonging infection, and in the metacyclic population by generating diversity that may counter existing partial immunity in reservoir hosts. Antigenic variation employs a huge repertoire of VSG genes. Only one is expressed at a time in bloodstream trypanosomes, as a result of transcription being restricted to a set of about 20 bloodstream expression sites (BESs), which are at chromosome telomeres. Only one BES is active at a time, probably through transcriptional elongation being inhibited in the silent BESs. Although transcriptional switching between BESs can effect a VSG switch, the most prolific switch route involves homologous recombination of deoxyribonucleic acid, usually by the copying of a silent gene into a BES. Hierarchical expression of VSGs may be dictated in part by the different types of locus occupied by VSG genes. The VSG genes expressed in the metacyclic population also occupy telomeric sites, which appear to be derived from BESs but have a simpler structure. Their differential expression is achieved by random transcriptional activation; the detailed story requires direct study of the metacyclic stage itself. Available evidence suggests that the VSG originated as a surface receptor, and it can be proposed that a number of selective events have contributed to the evolution of the complex, multisystem phenomenon that antigenic variation has become.