As described above for some bacterial pathogens (see Section 1319), Trypanosoma brucei, a causative agent of trypanosomiasis, or sleeping sickness, has evolved a remarkable capacity for antigenic variation to evade the antibody response elicited in infected humans. The trypanosome is coated with a single type of glycoprotein, the variantspecific glycoprotein (VSG), which elicits a potent protective antibody response that rapidly clears most of the parasites. The trypanosome genome, however, contains about 1000 VSG genes, each encoding a protein with distinct antigenic properties. A VSG gene is expressed by being placed into the active expression site in the parasite genome. Only one VSG gene is expressed at a time, and it can be changed by a gene rearrangement that places a new VSG gene into the expression site (Fig. 13.21). So, under the selective pressure of an effective host antibody response, the few trypanosomes within the population that express a different VSG escape elimination and multiply to cause a recurrence of disease (see Fig. 13.21, bottom panel). Antibodies are then made against the new VSG, and the whole cycle is repeated, resulting in periods of active and quiescent disease. The chronic cycles of antigen clearance lead to immunecomplex damage and
Fig. 13.21 Antigenic variation in trypanosomes allows them to escape immune surveillance. the surface of a trypanosome is covered with a variant-specific glycoprotein (VSG). each trypanosome has about 1000 genes encoding different VSGs, but only the gene in a specific expression site within the telomere at one end of the chromosome is active. although several genetic mechanisms have been observed for changing the VSG gene expressed, the usual mechanism is gene conversion. an inactive gene, which is not at the telomere, is copied and transposed into the telomeric expression site, where it becomes active. When an individual is first infected, antibodies are raised against the VSG initially expressed by the trypanosome population. a small number of trypanosomes spontaneously switch their VSG gene to a new type, and although the host antibody eliminates the initial variant, the new variant is unaffected. as the new variant grows, the whole sequence of events is repeated.
inflammation, and eventually to neurological damage, resulting finally in the coma that gives sleeping sickness its name. The cycles of evasive action make trypanosome infections very difficult for the immune system to defeat, and they are a major health problem in Africa.
Caused by Plasmodium species, malaria is another serious and widespread disease. Like Trypanosoma brucei, Plasmodium species vary their antigens to avoid elimination by the immune system. In addition, plasmodia undergo different parts of their life cycle in different cellular hosts within humans. Initial infection is by the sporozoite form of the organism, which is transmitted by the bite of an infected mosquito and targets hepatocytes in the liver. Here, the organism replicates rapidly to produce merozoites that burst from infected hepatocytes to infect circulating red blood cells. Thus, as the immune system focuses it efforts on the eradication of the parasite in the liver, the parasite morphs and escapes to its second cellular host, red blood cells. And because red blood cells are the only cells in the body that lack MHC class I molecules, antigens produced by the merozoites within infected red blood cells escape detection by CD8 T cells, preventing cytotoxic destruction of the infected cells. This represents one of the most elegant adaptations to evade cellmediated immunity.