Antigenic Variation in Vector-Borne Pathogens

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´╗┐Antigenic Variation in Vector-Borne Pathogens
The requirement for vector transmission of these infectious pathogens provides a powerful selection for mechanisms that prolong parasitemia. Through convergent evolution, several vector-borne pathogens have arrived at the same strategy of antigenic variation to achieve this goal. The similarity in the genetic mechanisms that such unrelated pathogens as African trypanosomes and relapsing fever Borrelia spp. use for antigenic variation is remarkable.

Antigenic variation has important implications for the development of vaccines against these pathogens. If the variable antigen is to be the target of immunoprophylaxis, the vaccine would likely need to be multivalent, perhaps to the point of impracticality. If the infected host animal has not solved the problem of identifying an antigen that is conserved among the variants, thereby neutralizing the infection earlier, how can vaccine developers hope to do this?

A possible way to meet this challenge is to focus on the function domains of the variable proteins. The variable antigens of both the bacterial and parasite pathogens have other roles in pathogenesis besides immune evasion. These include tissue tropism, shielding of adjacent molecules, inhibition of phagocytosis, modulation of antigen presentation, and selective adherence. Certain regions of the variable protein may be irrelevant for these functions of the pathogen, and consequently the encoding DNA sequences could be highly divergent among alleles. On the other hand, the regions conferring these functions would likely be more constrained in structure and thus comparatively more susceptible to cross-reacting antibodies.

Another possible way to meet the challenge of antigenic variation is to focus on the vector-specific surface antigens of these pathogens. The repertoire expressed in the arthropod vector, which lacks an adaptive immune system, is generally more limited than that expressed in the vertebrate host. The Lyme disease vaccine is an example of successful targeting of a vector-specific protein. Although B. burgdorferi has not yet been proven to undergo true antigenic variation, there is considerable diversity in the ospC sequences that define strain identity within a given area in which transmission to humans occurs. A vaccine based on OspC would likely need to be multivalent. In contrast, B. burgdorferi's OspA protein, the sole protein in the vaccine, is natively expressed in the tick's midgut but usually not during infection of mammals. Perhaps because of OspA's infrequent encounters with the mammalian adaptive immune system in nature, there is little divergence in ospA sequences between strains of B. burgdorferi. The OspA-based vaccine apparently works by eliciting antibodies that kill or inhibit the spirochetes in the tick, before expression of the more polymorphic ospC and vlsE genes in the mammalian host.

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