MECHANISMS OF ANTIGENIC DIVERSITY IN TRYPANOSOMA BRUCEI

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Trypanosomiasis is a severe constraint to human and livestock development in many parts of Africa. Development of immunity to the parasite is ineffective because of antigenic variation, due to changes in sequence of a surface glycoprotein (the variable surface glycoprotein or VSG). The genes coding for VSGs can evolve rapidly. Therefore, a particular VSG gene may be represented in many different stocks or in only a few. Also, the VSG gene may exist as an identical copy in each stock or as a partially homologous gene copy. The molecular mechanisms generating diversity in the VSG gene repertoire are not clearly understood, although evidence has been obtained for both gene conversion and point mutation. Trypanosomes have been isolated from the same serodeme which share variable numbers of exposed, surface epitopes. The expressed VSG genes in these trypanosomes may be examples of evolving genes whose sequence relationship to genes in the progenitor organism is still apparent. The structure of VSG genes in the progenitor organism and in the related progeny will be compared to suggest mechanisms by which VSG genes evolve, and by which the trypanosome continues to present new epitopes to the host immune system. The methodology will involve cloning of VSG genes and cDNAs from progenitor trypanosome and the serologically progeny. The cloned DNAs will be compared by restriction enzyme and S1 nuclease mapping. The specific aims are: (a) to isolate five cloned populations of Trypanosoma brucei from one serodeme which share exposed surface epitopes; (b) to determine whether complete basic copies of the genes responseble for expression of each of the five related VSGs pre-exist in the progenitor organism; and (c) where complete basic copies do not exist in the progenitor organism, to define the mechanisms by which the expressed VSG gene is produced. The mechanisms of surface antigen diversity in trypanosomes may be of wide significance in other persistent infectious diseases where the biochemical basis of persistence is not as well defined.