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.

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Harrington, Whitney E; Fried, Michal; Duffy, Patrick E (2016) Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy. J Infect Dis 213:496-7
Brickley, Elizabeth B; Wood, Angela M; Kabyemela, Edward et al. (2015) Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia. J Infect Dis 211:436-44
Gullingsrud, Justin; Milman, Neta; Saveria, Tracy et al. (2015) High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes. J Infect Dis 211:1134-43
Gonçalves, Bronner P; Huang, Chiung-Yu; Morrison, Robert et al. (2014) Parasite burden and severity of malaria in Tanzanian children. N Engl J Med 370:1799-808
Gonçalves, Bronner P; Fried, Michal; Duffy, Patrick E (2014) Parasite burden and severity of malaria in Tanzanian children. N Engl J Med 371:482
Kabyemela, Edward; Gonçalves, Bronner P; Prevots, D Rebecca et al. (2013) Cytokine profiles at birth predict malaria severity during infancy. PLoS One 8:e77214
Fried, Michal; Avril, Marion; Chaturvedi, Richa et al. (2013) Multilaboratory approach to preclinical evaluation of vaccine immunogens for placental malaria. Infect Immun 81:487-95
Obiakor, Harold; Avril, Marion; Macdonald, Nicholas J et al. (2013) Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay. Clin Vaccine Immunol 20:433-42
Saveria, Tracy; Oleinikov, Andrew V; Wiliamson, Kathryn et al. (2013) Antibodies to Escherichia coli-expressed C-terminal domains of Plasmodium falciparum variant surface antigen 2-chondroitin sulfate A (VAR2CSA) inhibit binding of CSA-adherent parasites to placental tissue. Infect Immun 81:1031-9
Harrington, Whitney; McGready, Rose; Muehlenbachs, Atis et al. (2012) Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis 55:1025-6; author reply 1026-7

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