Plasticity and diversity of the Plasmodium falciparum placental malaria antigen VAR2CSA
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As long as humans have walked this earth, malaria may have stalked them. Malaria is a disease of poverty and underdeveloped countries. Today, half of the world population lives in regions at risk for developing malaria and more than half a million deaths occur annually due this disease. Malaria is unforgiving, as most of the morbidity and mortality occurs in pregnant women and children under the age of five years. The majority of malaria-related deaths occur in Sub-Saharan Africa because there is limited access to effective vaccine and treatment. The malaria parasite evades host immune defenses through antigenic variation of proteins called Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1). These proteins are expressed on the surface of infected erythrocytes, which allow them to bind to various host tissues. The proteins are encoded by a highly polymorphic var (variant) gene family, consisting of ~60 genes. While polymorphic, one of these genes, var2csa, is the most conserved PfEMP1 identified to date. The genes ancient origin and evolutionary significance is indicated by the fact that an ortholog is found in the genome of chimpanzee malaria P. reichenowi. VAR2CSA is only expressed during pregnancy. In pregnant women, Plasmodium falciparum is able to bind to a unique low sulfated form of chondroitin in the placenta by expressing VAR2CSA on the surface of the infected erythrocyte. The massive sequestration of these erythrocytes in the placenta results in pregnancy complications, including low-birth weight (LBW), maternal and neonatal death. While women in their first and second pregnancies are at highest risk for developing placental malaria (PM), partial immunity is achieved after multiple pregnancies through protective antibodies. This suggests that a vaccine to protect against placental malaria (PM) may be feasible. The dissertation herein provides detailed information on the genetic complexity of PM and methods of identifying and constructing representative allelic variants of VAR2CSA that may be used as a vaccine to protect mothers and their fetuses from placental malaria.