The identification of novel variant surface antigens of Plasmodium falciparum.

摘要

Plasmodium falciparum utilizes sequence diverse and variantly expressed surface antigens (VSA) as a means to escape host immune recognition giving rise to persistent infections in humans. To date, investigations into the immune response to malarial infection have focused on a limited number of previously identified antigens. With a large portion of the genome remaining uncharacterized, we sought a genome-wide approach to identify novel VSA to better understand the parasite's antigen repertoire and inform studies of acquired immunity and malaria pathogenesis.;To identify novel antigens, we focused on genes with high nucleotide diversity and non-synonymous to synonymous SNP ratio. Additional bioinformatics parameters such as expression, predictors of membrane association, and cellular localization were also considered. A testable set of candidates were selected and further evaluated for signatures of diversifying selection.;We also investigated whether the candidate antigens are targeted by the host immune response during natural infection. Each of the antigens investigated was specifically recognized by IgG in plasma samples from malaria infected individuals. These results indicated that our genomic approach was successful in identifying novel antigens targeted by the host immune response.;The variant expression of surface antigens is utilized by numerous pathogens, and contributes to the ability of the organism to evade the host immune response. We investigated the role of variant expression of one of our candidate antigens, a member of the Hyp15 family. We found the Hyp15 expression profile to differ between individual clones and that the expression profile of individual clones changed over time. These results indicate that the Hyp15 family is clonally variant and can undergo expression switching.;This dissertation demonstrates the successful application of genomics approaches to identify novel antigens. Biological follow-up of the candidates validated our approach and showed that the candidate antigens are specifically recognized during natural infection. Additional characterization indicates that one of our candidates represents a novel family of variant surface antigens in P. falciparum. These studies allow us to better understand the full antigen repertoire of Plasmodium falciparum and provide a more complete toolset with which to evaluate acquired immunity and develop interventions to this important disease.