Investigating HLA-I as a driver of P. falciparum antigenic diversity - PROJECT SUMMARY Plasmodium falciparum, the causative agent of the most virulent form of malaria, harbors highly genetically diverse antigens. While immune selection likely sustains this diversity, the specific immune mechanisms patterning it and its implications for vaccine interventions remain to be established. In some antigens, dominant variants differ across geographic regions but alternate little over time. This pattern suggests that antigens may locally adapt to host populations. We hypothesize that antigens adapt to host population composition at the HLA-I locus, which governs the ability of the immune system to present parasite peptides to sterilizing cellular effectors. To test this hypothesis, we first examine infections across a transmission season in an intensively longitudinally sampled cohort. Using amplicon sequencing of four highly polymorphic parasite antigens and HLA typing data from hosts, we will test for interactions between specific parasite antigen and host HLA-I residues that influence infection or clinical outcomes, and furthermore screen HLA-I as a functional driver of parasite diversity at the population level. Subsequently, we will pair pathogen and host genomic variation datasets from the MalariaGEN Pf7 database and Allele Frequency Net Database, respectively. Using HLA-I binding prediction tools, we will compare the peptidomes of potential HLA-I and parasite antigen combinations and gauge the influence of host and pathogen allele frequencies on predicted binding parameters, testing for the presence of parasite local adaptation to hosts. Finally, we will use yeast display to perform in vitro functional validation of changes in HLA-I binding with parasite variation across a large library of peptides. This project will provide functional insight into the drivers and immunological impacts of parasite variation relevant to vaccine design.
