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 We report the following advances in FY2023: 1. Based on our previous finding (Mahamar et al 2021) that circulating 20S proteasome levels are significantly higher in children with hemoglobin loss compared to children with stable hemoglobin we set up in vitro system to examine circulating 20S proteasome activity on plasma proteins under varying oxidative stress condition. That includes, optimizing oxidation condition and degradation conditions. 2. We used bioinformatic tools to identify potential PfEMP1s CIDRa domains mediating parasite adhesion to CD36 based on our proteomic analysis of clinical parasite isolates. 15 recombinant CIDRa domains were expressed in eukaryotic expression system and additional 8 domains are in the process of cloning and expression in eukaryotic system. Immune responses to these domains will be related to protection from malaria disease. 3. We used proteomics tools to identify conserved and variant antigens recognized by childrens antibody. Combined global proteomic analysis of clinical parasite isolates and immunoprecipitation studies of falciparum membrane proteins, a list of top 10 proteins was selected. These proteins are currently being expressed using eukaryotic expression system. 4. Between August-December 2022, 160 hospitalized children with severe malaria and community control children with mild malaria were enrolled to expand our studies of malarial anemia pathogenesis.