Trypanosomiasis: Parasite, antigenic variation

When the parasite is present in an individual, it is covered with a thick monotonous layer of a single type of glycoprotein, VSG or Variant Surface Glycoprotein. These glycoproteins consist of 400-500 aminoacids and various saccharide groups and are anchored into the cell membrane with a so-called GPI-anchor (glycosyl-phosphatidyl-inositol). Ten percent of the proteins of the trypanosome consist of VSG. The entire VSG surface of a trypanosome is recycled every seven minutes by a process of VSG endocytosis and exocytosis. When the parasite is transferred to the tsetse fly, the VSG coating disappears within 4 hours and is replaced by an invariant glycoprotein ("procycline" or PARP). After the parasite has completed its cycle in the fly and arrives into the latter’s salivary glands, the VSG coating reappears. The VSG coating is of vital importance for the parasite when it is in the vertebrate host. This explains why only metacyclic trypanosomes (the mature forms in the salivary glands of the insect) are infectious. When an antigenically homogeneous population of parasites is in the human body, antibodies against the VSG of this population are produced. The immune system lyses the parasites ( fever episode). Infections with trypanosomes would be cured quickly, if the parasite population could not constantly change its surface antigens.

The parasite has about 1000 genes that code for different VSGs and thus has a vast repertoire of surface antigens. Most of these genes are located on some hundred minichromosomes in the nucleus of the parasite. The parasite also has about twenty chromosomes of "normal" size. These do not condense during mitosis. At any one time only one VSG gene per parasite is active. A few trypanosomes in a population have a different VSG (heterologous variants). After destruction of the first, dominant population by the immune system, the heterologous parasites increase in number until the variant VSG has induced antibodies and a new cycle of destruction begins. A third population of minority variants then emerges. This antigenic variation is a very important factor in the development of the disease and explains various symptoms (including its chronic course, fluctuating parasitaemia and fever episodes).

The order in which antigenic variants appear is partially pre-determined. Alteration of surface antigens is not induced by antibodies but occurs spontaneously. The genetic mechanism that the parasite uses for this is very complex. The gene that is to be expressed is duplicated from a locus on one of the chromosomes to a subtelomeric locus (close to one end of a chromosome). The mRNA originating from the gene on this latter locus is subsequently coupled ("trans-splicing") to a small mRNA fragment that is coded elsewhere. This small fragment (mini-exon) is the same for all VSGs. The mechanism for mutually exclusive activation of the VSG genes is still not known. Some other genetic mechanisms are linked to this. An unusual DNA-pyrimidine base ("J"; compare with A, T, G and C) is present in small quantities in the trypanosome genome and occurs more frequently in the telomeres. The unusual nucleotide is present only in the blood form, not in the procyclic form. The significance of this is not yet known.

It is important for the parasite to keep the population in the host as homogeneous as possible in order to use the VSGs economically. However, when parasites infect a host, diversity is advantageous. Hence, some 20 different variants can be present in the saliva of a fly. Any one of these variants is capable of infecting a host provided there are no antibodies present from a previous infection. If the host is immunologically naive to trypanosome antigens, the same VSG eventually dominates the first parasitic population.

Category: Medicine Notes