The roles of secreted antibody and bir variant antigens in immunity to Plasmodium berghei

Billions of people are at risk of contracting malaria each year, and we now face the ever-increasing resistance of mosquitoes to insecticide and parasites to the available chemotherapies. Despite decades of work toward a vaccine, there is still no fully effective human vaccine for this disease that has plagued humans since prehistoric times. The first section of this project attempted to understand the basis of immunity achieved in the rodent by infection and cure. We re-examine the original model of infection and cure in the rodent with the modern tools of mouse genetic manipulation that were not available when the model was established. We demonstrate the crucial role played by secreted antibody in the development of immunity. The next two sections of this project focus on the parasite side of immunity and the antigens that are potential targets of the secreted antibody described in Chapter 1. One variant antigen family, pir ( Plasmodium interspersed repeat), has been identified in at least six Plasmodium species, which infect humans, primates, and rodents. We hypothesized that the target of the secreted antibody required for immunity is the pir family homologue in P. berghei, the bir genes. In Chapter 2, we describe our characterization of the bir gene family: a phylogenetic and expression analysis that utilized the parasite populations generated by our infection and cure mouse model. We demonstrate that multiple bir genes are expressed at once in a population of bir genes and that the immune status of the host does not influence the bir gene repertoire, suggesting that the bir genes do not function as a canonical variant antigen family. In Chapter 3, we test our hypothesis that the BIR proteins are the target of secreted antibody. We found that one of the BIR proteins is immunogenic and antibodies are raised against it during natural infection. Immunization with this BIR protein was unable to protect mice against infection. Taken together, our findings suggest that the bir family is not the primary target of the immunity generated by mice during infection and cure.