Malaria Pathogenesis in Pregnant Women and Young Children

National Institute Of Allergy And Infectious Diseases

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Abstract

The study aims at identifying protective immune responses that reduce malaria disease and parasite burden in young children. This study is based on our earlier studies of pregnancy malaria. Susceptibility to pregnancy malaria (PM) results from the unique binding phenotype of placental parasites that adhere to chondroitin sulfate A (CSA). Over successive pregnancies, women develop specific humoral immunity to placental parasites in the form of anti-adhesion antibodies. Anti-adhesion antibodies are associated with improved pregnancy outcomes. To better understand malaria pathogenesis in pregnant women, and the development of immunity in young children, we established a longitudinal birth cohort in Mali in which women were enrolled during their pregnancy and their newborn children actively followed up from birth up to 5 years. Blood samples collected from pregnant women and children at fixed time points and at the time of infection are used to: 1. Assay soluble mediators; 2. Describe parasite binding phenotype; 3. Characterize parasite membrane proteome; 4. Measure anti-adhesion antibodies; 5. Assess disease biomarkers From our publications this year, we report the following advances in FY2021: 1. Mahamar A, Andemel N, Swihart B, Sidibe Y, Gaoussou S, Barry A, Traore M, Attaher O, Dembele AB, Diarra BS, Keita S, Dicko A, Duffy PE, Fried M. Malaria infection is common and associated with perinatal mortality and preterm delivery despite widespread use of chemoprevention in Mali: an observational study 2010 to 2014 Clin Infect Dis 2021. doi: 10.1093/cid/ciab301 Pregnancy malaria, especially in non-immune first-time mothers, often results in low birth weight and maternal anemia, which have been extensively described. Knowledge on the association between malaria infection with Plasmodium falciparum and severe outcomes such as miscarriage, stillbirth and early neonatal death is limited. A previous meta-analysis suggested that malaria infection is responsible for 20% of stillbirths in sub-Saharan Africa regardless of gravidity or malaria prevention. Here, in the context of a longitudinal cohort study of 1850 pregnant women conducted in Oulessbougou, Mali, an area with high seasonal malaria transmission, we relate gravidity-dependent association between malaria infection during pregnancy in women that received anti-malarial drug as part of a chemoprevention program, and treatment when infected and severe outcomes: miscarriage, stillbirth, early neonatal death and preterm delivery. We show that malaria infection increased the risk of stillbirth and preterm delivery in primigravidae (adjusted HR 3.87, p=0.03; aHR 2.41, p=0.003 respectively), and increased the risk of early neonatal death in secundigravidae and multigravidae (aHR 6.30, p=0.02). These results suggest that treatment and intermittent preventative treatment alone are insufficient to prevent poor pregnancy outcomes such as stillbirth and preterm delivery and highlights the need for additional measures like a pregnancy malaria vaccine. 2. Araj BN, Swihart B, Morrison R, Gonzales PH, Teo A, Mahamar A, Attaher O, Diarra BS, Gaoussou S, Issiaka D, Dicko A, Duffy PE, and Fried M. Antibody Levels to Plasmodium falciparum Erythrocyte Membrane Protein 1-DBL11 and DBL-1 Predict Reduction in Parasite Density. mSystems 2021. 6(3):e0034721. doi: 10.1128/mSystems.00347-212021. In this paper, we describe a new approach to identify PfEMP1 targets of protective immunity. This approach is based on utilizing proteomics data of clinical parasite isolates infecting young children, that was then used to identify PfEMP1 domains expressed by these parasites, followed by design of a peptide library for immunosurvey. Antibody levels to the peptides were measured in plasma samples of young children participating in a longitudinal birth cohort. Antibody levels were related to the childs infection history and more importantly, assessed as a predictor of disease severity in future infections. We demonstrate that antibody levels against two peptides representing two PfEMP1 domains predicted a significant reduction in parasite burden in future infections. Our unpublished progress during this reporting period includes the following advances: 1. We evaluated if antibody levels toward two conserved antigens (a member of PHIST family and the FIKK family) commonly expressed in P. falciparum isolates collected from infected children are associated with reduced parasite burden and reduced risk of severe malaria. We found that levels of IgM to the PHIST had a significant but modest effect on reduction in parasite density. 2. We sought to understand the pathways associated with malarial anemia. We conducted a quantitative proteomic analysis of plasma samples from malaria-infected children that did or did not experience an acute drop in hemoglobin levels. Using this approach we identified novel biomarkers supporting the model that both hemolysis and insufficient erythropoiesis contribute to malarial anemia.