A forward genetic screen reveals a primary role for Plasmodium falciparum Reticulocyte Binding Protein Homologue 2a and 2b in determining alternative erythrocyte invasion pathways

• DOI: 10.1371/journal.ppat.1007436
• Publication Date: 2018-11-29T19:10:56Z
• Authors: Susana Campino; Alejandro Marin-M...; Alison Kemp; Nadia Cross; Laura Drought; Thomas D. Otto; Ernest Diez Benav...; Matt Ravenhall; Frank Schwach; Gareth Girling; Magnus Manske; Michel Theron; Kelda Gould; Eleanor Drury; Taane G. Clark; Dominic P. Kwiatk...; Alena Pance; Julian C. Rayner
• Keywords: Candidate gene

Invasion of human erythrocytes is essential for Plasmodium falciparum parasite survival and pathogenesis, also a complex phenotype. While some later steps in invasion appear to be invariant essential, the earlier recognition are controlled by series redundant, only partially understood, receptor-ligand interactions. Reverse genetic analysis laboratory adapted strains has identified multiple genes that when deleted can alter invasion, but how relative contributions each gene translate phenotypes clinical isolates far from clear. We used forward approach identify responsible variable erythrocyte phenotyping parents progeny previously generated experimental crosses. Linkage using whole genome sequencing data revealed single major locus was majority phenotypic variation two pathways. This contained PfRh2a PfRh2b genes, members one ligand families, not widely thought play such prominent role specifying phenotypes. Variation pathways linked significant differences expression between lines, their alternative confirmed CRISPR-Cas9-mediated editing. Expansion large set P. common deletions, suggesting at this cause endemic setting. work implications blood-stage vaccine development will help inform design location future large-scale studies isolates.