gene b copied to number of parasites levels of antibodies x1000 VSGb gene c copied to expression site infection manages a 2% change in its genome in 5 days—about the time it takes the virus to pass from the human mouth to the gut. Second, selective pressures act rapidly on this genetic variation. The host’s adaptive immune system and modern microbicidal drugs, both of which destroy pathogens that fail to change, are the main sources of these selective pressures.
An example of an adaptation to the selective pressure imposed by the adaptive immune system is the phenomenon of antigenic variation. An important adaptive immune response against many pathogens is the host’s production of antibodies that recognize specific molecules (antigens) on the pathogen’s surface (discussed in Chapter 24). Many pathogens have evolved mecanisms that deliberately change these antigens during the course of an infection, enabling them to evade antibodies. Some eukaryotic parasites, for example, undergo programmed rearrangements of the genes encoding their surface antigens. A striking example occurs in Trypanosoma brucei, a protozoan parasite that causes African sleeping sickness and is spread by tsetse flies. (T. brucei is a relative of T. cruzi—see Figure 23–21—but it replicates extracellularly rather than intracellularly.) T. brucei is covered with a single type of glycoprotein, called variant-specific glycoprotein (VSG), which elicits in the host a protective antibody response that rapidly clears most of the parasites. The trypanosome genome, however, contains about 1000 different Vsg genes or pseudogenes, each encoding a VSG with a distinct amino acid sequence. Only one of these genes is expressed at any one time, from one of approximately 20 possible expression sites in the genome. Gene rearrangements that copy different Vsg genes into expression sites repeatedly change the VSG protein displayed on the surface of the pathogen. In this way, a few trypanosomes with an altered VSG escape the initial antibody-mediated clearance, replicate, and cause the disease to recur, leading to a chronic cyclic infection (Figure 23–30).
Bacterial pathogens can also rapidly change their surface antigens. As discussed in Chapter 5, Salmonella enterica bacteria switch between expressing either of two versions of the protein flagellin, the structural component of the bacterial flagellum (see Figure 23–3D), in a process called phase variation (see Figure 5–65). Species of the genus Neisseria are also champions at this. These Gram-negative cocci can cause meningitis and sexually transmitted diseases. They undergo genetic recombination very similar to that just described for eukaryotic pathogens, which enables them to vary the pilin protein they use to attach to host cells. By inserting one of the multiple silent copies of variant pilin genes into a single expression locus, they can express many slightly different versions of the protein and repeatedly change the amino acid sequence over time. Neisseria bacteria are
Figure 23–30 antigenic variation in trypanosomes. (A) There are about 1000 distinct Vsg genes in Trypanosoma brucei, and they are expressed one at a time from approximately 20 expression sites in the genome. To be expressed, an inactive gene is copied and the copy is moved into an expression site through DNA recombination. Each Vsg gene encodes a different surface protein (antigen). These switching events allow the trypanosome to repeatedly change the surface antigen it expresses. (B) A person infected with trypanosomes expressing VSGa mounts a protective antibody response, which clears most of the parasites expressing this antigen. However, a few of the trypanosomes will have switched to expression of VSGb, which can now proliferate until anti-VSGb antibodies clear them. By that time, however, some parasites will have switched to VSGc, and so the cycle continues.