Pregnancy Malaria: Pathogenesis and Immunity

妊娠期疟疾影响全世界约5 000万妇女，每年造成20万婴儿死亡。由于胎盘中与恶性疟原虫结合的硫酸软骨素A （CSA）被隔离，PM增加了产妇贫血、死产、自然流产、低出生体重、新生儿死亡和先兆子痫的风险。先前的离体实验表明，用疟疾流行地区的多孕妇女或免疫寄生虫黏附关键抗原的动物血清治疗寄生虫，可以抑制CSA在胎盘中的结合机制。

Pregnancy malaria (PM) affects estimated 50 million women worldwide and contributes to 200,000 infant deaths annually. Caused by sequestration of chondroitin sulfate A (CSA) binding Plasmodium falciparum parasites in placenta, PM increases risks of maternal anemia, stillbirth, spontaneous abortion, low birth weight, neonatal death, and preeclampsia. Previous ex vivo experiments have shown the mechanism of CSA binding in placenta can be inhibited by treating parasites with sera from multigravida women of malaria endemic area or animals immunized with antigens critical for parasite adhesion. LMIV is committed to develop pregnancy malaria vaccines that will protect women through production of anti-adhesion antibodies.During the past fiscal year, LMIV scientists have accomplished the following: 1. Established two novel animal models of pregnancy malaria. Using a panel of P. chabaudi isolates (heterologous strains AS, CB and ER have been under study), we have developed a mouse model of both malaria recrudescence and malaria reinfection during pregnancy in C57BL6 mice, and have found that malaria severity and poor outcomes are related to production of inflammatory cytokines such as TNFa and MCP1, and the anti-inflammatory cytokine IL10. Separately, we have developed the first ever non-human primate model of placental malaria, by showing the sequestration of P. falicparum parasites in the placenta of pregnant Aotus monkeys. 2. VAR2CSA is the primary determinant of P. falciparum adhesion to the placental receptor CSA. Recently, we have examined whether other parasite proteins contribute to the CSA-binding phenotype and now describe PfCSA-L as a novel surface antigen that associates with VAR2CSA on the surface knobs of Pf-IE. Over the past year, we have shown that PfCSA-L binds with high affinity to human placental CSPG by Surface Plasmon Resonance (SPR). Duo-Link analysis using DBL2X and PfCSA-L antibodies indicates that the proteins interact with each other; SPR analysis reveals that the DBL2X domain of VAR2CSA binds to PfCSA-L with subnanomolar affinity. Urea extraction of Pf-IE membranes suggests that both VAR2CSA and PfCSA-L are anchored by protein-protein (rather than protein-lipid) interactions on the IE surface , suggesting that they exist in complexes. Both VAR2CSA and PfCSA-L membrane proteins are resistant to alkaline sodium carbonate extraction, a hallmark of integral membrane proteins. These findings suggest that PfCSA-L interacts with VAR2CSA on surface knobs of Pf-IE, where it may contribute to the CSA-binding phenotype. As a highly conserved protein of small size (25 kDa), PfCSA-L appears to be a valuable target for placental malaria vaccine development.