Pregnancy malaria is an overwhelming public health problem in tropical countries, which has been related to disease and mortality for both the mother and her child. Malaria induces inflammatory responses in primigravid women (who suffer from the disease). High TNF-1 levels in the placenta are associated with maternal anemia in primigravidas but not in multigravidas. We hypothesize that proinflammatory signaling pathways in primigravid women modify the expression of erythropoiesis-specific factors in the placenta, leading to anemia through one or both of the following pathways. 1. Inflammatory cytokines and other macrophage mediators suppress the expression of placental factors that regulate erythropoiesis. 2. Parasite adhesion to placental syncytiotrophoblast directly modulates the expression of placental factors that regulate erythropoiesis. Proteomics studies constitute a nonbiased approach to investigate differences in global protein expression. Here we will examine placental plasma proteome changes related to malarial anemia pathway at the site of parasite sequestration and inflammation-the placenta. Specifically, the study will examine 1. Changes in placental plasma proteome associated with malarial anemia by using quantitative proteomics tools. 2. Characterize the secretome of placental immune cells by quantitative proteomics. 3. Confirm that malaria anemia pathway proteins are associated with malaria anemia in cohorts of Tanzanian women. Based on these hypotheses we expect, that the relative abundance of transcription factors, growth factors and immunomodulators in placental blood associated with erythropoiesis will correlate with maternal hemoglobin levels. We expect that macrophage-specific mediators that modify erythroid proliferation and development will be more abundant in placental blood samples from primigravidas. Pregnancy malaria is the best-understood malaria syndrome. The characterization of the plasma proteome in malaria-infected pregnant women will contribute to our understanding of the host-pathogen interaction in the pregnant host, and will generate information for larger studies of novel molecules involved in the pathogenesis of severe anemia in children.

Public Health Relevance

In malaria endemic areas, pregnancy malaria is a risk factor for maternal mortality due to anemia. Pregnancy malaria and maternal anemia are independent risk factors for low birth weight (LBW) deliveries that increase the risk of mortality during the neonatal period and infancy. This study will identify potential immunological and transcriptional pathways and mediators that are pivotal in the pathogenesis of malaria associated maternal anemia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Signore, Caroline
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Seattle Biomedical Research Institute
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Lybbert, Jared; Gullingsrud, Justin; Chesnokov, Olga et al. (2016) Abundance of megalin and Dab2 is reduced in syncytiotrophoblast during placental malaria, which may contribute to low birth weight. Sci Rep 6:24508
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
Dong, Shu; Kurtis, Jonathan D; Pond-Tor, Sunthorn et al. (2012) CXC ligand 9 response to malaria during pregnancy is associated with low-birth-weight deliveries. Infect Immun 80:3034-8
Simpson, David C; Kabyemela, Edward; Muehlenbachs, Atis et al. (2010) Plasma levels of apolipoprotein A1 in malaria-exposed primigravidae are associated with severe anemia. PLoS One 5:e8822