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 FY2022: 1. Mahamar M, Gonzales Hurtado PA, Morrison R, Boone R, Attaher O, Diarra BS, Gaoussou S, Issiaka D, Alassane Dicko A, Duffy PE, Fried M. 2021. Plasma biomarkers of hemoglobin loss in Plasmodium falciparum-infected children identified by quantitative proteomics. Blood doi:10.1182/blood.2021014045 In high malaria transmission zones, moderate anemia is more common than severe malaria among young children. Anemia in young children is a major global health problem that impairs their health and development. Previous studies suggest that hemolysis of uninfected red blood cells (URBC) and/or insufficient erythropoiesis are the major causes of severe malarial anemia (SMA). Our goal is to better understand the pathways related to an abrupt hemoglobin loss during malaria infection, resulting in moderate or severe anemia. Our working hypothesis is that common pathways are associated with an acute drop in hemoglobin regardless of anemia severity. Our research plan includes employing quantitative proteomic tools to identify soluble mediators associated with hemoglobin loss pathways. We applied quantitative proteomics tools to compare the plasma proteome of samples collected from children with hemoglobin drop of >1.5 g/dl in hemoglobin compared to their previous measurement within 8 weeks with SMA (HDSMA); with hemoglobin loss without SMA defined as a reduction of >1.5 g/dl in hemoglobin compared to their previous measurement within 8 weeks. Stable hemoglobin among infected children was defined as a change of 1 g/dl in hemoglobin compared to the previous measurement within 8 weeks. Identified differentially expressed plasma proteins in children with HDSMA and HDNSMA by quantitative plasma proteomics. We determined that circulating 20S proteasome levels are significantly higher in children with HDSMA and HDNSMA compared to children with stable hemoglobin. Further chymotrypsin-like activity of c-20S proteasome was higher in HDSMA and HDNSMA. In addition, IGF-1 levels were significantly lower in children with HDSMA and HDNSMA compared to children with stable hemoglobin, and IL-18 levels were significantly higher in children with HDSMA and HDNSMA compared to children with stable hemoglobin. Based on the results, we propose a model in which circulating 20S proteasome plays a role in digesting modified membrane/cytoskeleton proteins of uninfected erythrocytes due to increased oxidative stress in response to infection, leading to hemolysis. In parallel, as IGF-1 plays an essential role in erythroid proliferation, reduction in IGF-1 levels may contribute to insufficient erythropoiesis. The combination of hemolysis and insufficient erythropoiesis contribute to reduction in hemoglobin during malaria infection. 2. Gonalves BP, Prez-Caballero R, Barry A, Gaoussou S, Lewin A, Issiaka D, Keita S, Diarra BS, Mahamar A, Attaher O, Narum DL, Kurtis JD, Dicko A, Duffy PE, Fried M. 2022. Natural history of malaria infections during early childhood in twins. J Infect Dis: doi: 10.1093/infdis/jiac294 Accounting for host and environmental factors contributing to susceptibility to malaria infection is complicated. In this paper, we took an approach that differs from previously published epidemiological studies. We describe data from birth of twins living in an area with seasonal malaria transmission in Mali. By selecting this special study population, matched in all relevant factors that are believed or known to influence malaria phenotypes (e.g. exposure to mosquitoes, host genetics, in utero environment), we quantified variation in the history of malaria infections and made comparative assessments within pairs. Our comprehensive analysis, in addition to longitudinal parasitological data up to the age of 5, also included serological measurements at multiple timepoints to evaluate acquisition of immunity in each twin. Using statistical modelling, we described that the risk of parasitemia vary between pairs but not within pairs. Further, in a twin pair in which one of the twins had a hemoglobin type HbAS and the other HbAA, the twin with HbAS consistently had lower parasite densities compared to the twin with HbAA, however, antibody levels to several malarial antigens were similar between these two twins. Our unpublished progress during this reporting period includes the following advances: 1. We measured antibody levels in plasma samples of young children participating in a longitudinal birth cohort to additional peptides derived from PfEMP1 detected by mass spectrometry analysis of clinical parasites (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. mSystems 2021. 6(3):e0034721. doi: 10.1128/mSystems.00347-212021). Antibody levels were assessed as a predictor of disease severity in future infections. Based on these results and previous data (Araj et al) we are in the process of designing recombinant PfEMP1 domains that will be further studied. 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. Immune responses to these domains will be related to protection from malaria disease. 3. We are evaluating changes in uninfected red blood cells associated with malaria anemia. Preliminary data is currently used to develop quantitative comparative tools.