Proteomic studies of Plasmodium knowlesi SICA variant antigens demonstrate their relationship with P. falciparum EMP1

Malaria variant antigens are encoded by large multigene families and expressed on the surface of infected erythrocytes. The Plasmodium knowlesi Schizont-infected cell agglutination (SICA) antigens are encoded by the SICAvar multigene family, and the P. falciparum erythrocyte membrane protein-1 (PfEMP1) antigens are encoded by the var gene family. Although these variant antigens share many fundamental features, P. knowlesi and P. falciparum are phylogenetically distantly related, and so far a significant level of sequence identity has not been observed in alignments of either the SICAvar and var gene families or their encoded proteins. In support of their orthologous relationship, however, here we demonstrate through proteomic analysis that the P. knowlesi SICA variant antigens share significant common sequences with P. falciparum EMP1 molecules. As many as forty P. knowlesi SICA peptides show identity with a particular P. falciparum EMP1, mapping throughout all characterized domains, including the externally exposed cysteine-rich domains that are characteristic of both proteins. These findings provide further validation of the classical in vivo P. knowlesi-rhesus monkey model system for advancing our understanding of the immunobiology of antigenic variation and variant antigen gene expression in Plasmodium.