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 FY2025: Barry A, Dang L, Sidibe Y, Issiaka D, Gaoussou S, Dicko Y, Mahamar A, Attaher O, Diarra BS, Keita S, Dicko A, Duffy PE, Fried M. Preterm birth increases malaria susceptibility in offspring of uninfected multigravidae. 2025. JAMA Network Open. In press. In this publication, we investigated the association of pregnancy malaria (PM) and preterm delivery (PTD) with child susceptibility to malaria infection and disease. Pregnant women in Ouélessébougou, Mali were enrolled between 2010-2014 into an observational longitudinal cohort study and followed through pregnancy. After delivery, children were followed from 2011 to 2016 for up to 5 years with monthly clinical visits during the malaria transmission season and every 2 months during the dry season. Cox proportional hazard models analyzed whether hazards of first malaria infection and first clinical malaria were associated with PM and with PTD. Study endpoints included Plasmodium falciparum infection, clinical malaria, and severe malaria infections. Malaria diagnosis and clinical data were collected during scheduled and unscheduled sick visits. In 1679 children included in adjusted models, 45.3% of children were born during the malaria transmission season and 96 children born preterm. On average, children were followed for 25.8 (SD 16.1) months. PM was associated with an increased hazard of first malaria infection and first clinical malaria in children of women of all gravidities, while PTD was associated with increased hazard of first infection by 1.76, (95% CI 1.05-2.95) p=0.03 in offspring of multigravidae only. Further, the hazard ratio of first parasitemia for pre-term compared to term offspring was 2.17 (95% CI 1.25-3.75), p=0.006 and 3.63 (95% CI 1.90-5.93), p<0.0001 in offspring of uninfected secundigravidae and multigravidae. The infection incidence rate ratio for PTD was 2.74 (95% CI 1.80-4.18) in offspring of uninfected multigravidae. In this cohort study of young children, the association between PTD and the hazard of malaria varied based on maternal gravidity and maternal infection history during pregnancy. This information could be used to evaluate health impacts of active monitoring of Plasmodium falciparum infection or adherence to malaria chemoprevention in children born preterm. Additional advances 1. To-date, few parasite proteins expressed by blood-stage parasites were evaluated as targets of protective immunity. We employed immunoprecipitation and mass spectrometry to identify new targets of protective immunity, followed by the selection of several candidate proteins for which there is limited or no prior information on their role in immunity to malaria. We then evaluated if antibody levels to these proteins measured in plasma samples of young children participating in a longitudinal birth cohort predict reduction in disease severity in future infections. We described that antibody levels against two PfEMP1 domains and two PHISTb proteins predicted reduction in parasite burden in future infections. Further, opsonic phagocytosis of PfEMP1-coated beads was significantly higher in plasma samples with high antibody levels than in samples with low antibody levels suggesting that opsonic phagocytosis may mediate reduction in parasite density by antibodies to the two PfEMP1 domains. This manuscript is currently under review. 2. We used proteomics and transcriptomics data of parasite isolates collected from malaria-infected children to identify potential PfEMP1’s CIDRa domains mediating parasite adhesion to CD36. Using various bioinformatic tools we selected CIDR sequences reflecting the variation of PfEMP1 expressed in parasites circulating in this population. These sequences will be used to express recombinant proteins in eukaryotic expression system that will then be used characterizing their binding to CD36 and relate immune responses to these proteins with clinical outcomes. 3. We have been studying the associations between levels of complement components and pregnancy outcomes. In this study we measured levels of several complement components representing the 3 complement pathways in samples collected from pregnant women using multiplex beads assay. Measuring levels of these factors is on-going.