Plasmodium knowlesi Ligand-Receptor Mechanism in the Placenta of Olive Baboons (Papio anubis) with Malaria in Pregnancy

Abstract

Pregnancy associated malaria (PAM) poses many risks to both women and their infants. It is characterized by accumulation of infected erythrocytes in placental intervillous spaces leading to adverse reactions. Studies using the P. knowlesi-Olive baboon model of pregnancy malaria have demonstrated this phenomenon though mechanisms and molecules involved are not known. This study sought to determine the ligands and receptor molecules that permit accumulation of infected erythrocytes in the placenta of P. knowlesi infected Olive baboons and to further test placental isolates for adhesion to purified receptors. Sequences of known Plasmodium erythrocyte binding antigens and human placental receptors were used in BLAST analysis against the genomes of P. knowlesi and P. anubis respectively. Hits generated were analysed and characterized to determine the prospective ligands and receptors in P. knowlesi and P. anubis respectively. Also, four adult female baboons (P. anubis) were infected with P. knowlesi parasites and their placentas sampled. Infected erythrocytes isolated from these placentas were tested for binding against purified receptors. The results revealed that Predicted chondroitin sulphate proteoglycan 4 (CSPG 4) partial and Predicted hyaluronan and proteoglycan link protein 1 (HAPLN 1) are the putative receptor molecules in the Olive baboon. Phylogenetic analyses clustered them together with sequences from macaques which are he natural hosts of P. knowlesi. They also had similar domain organization to known human receptors (CSA and HA). Further, the P. knowlesi erythrocyte binding proteins (EBP-alpha, EBP-beta and EBP-gamma) matched closely to the placental P. falciparum ligand Var2csa and showed similar domains. However, static binding assays with P. knowlesi infected erythrocytes did not show any binding to purified receptors. This study has identified and proposed receptors and ligands involved in the adherence mechanism in P. knowlesi infected Olive baboons during pregnancy. This presents the Olive baboon as a suitable model for studying PAM at the pre-clinical level and will be important in studies to develop PAM vaccines and therapeutic agents.