In 2015, malaria killed 292,000 children under five years of age in sub-Saharan Africa. Hemoglobinopathies provide protection against malarial disease and reflect the powerful selective force of malaria on the human genome. In rural Mali, hemoglobin C trait provides protection against severe malaria and uncomplicated malaria illness. The precise mechanisms that protect children with hemoglobin C trait against malaria illness is unclear, but appear to be linked to Plasmodium falciparum malaria parasite variant antigens on the surface of infected erythrocytes that play a critical role in mediating disease severity. These variant surface antigens bind to host receptors in the endothelial membrane, facilitating tissue sequestration and avoidance of splenic clearance. The natural acquisition of immunity to P. falciparum malaria in infants and young children likely depends on the development of protective antibody responses against these variant surface antigens. Hemoglobin C trait decreases the quantity of these antigens on the surface of infected erythrocytes and alters their display. We have found that Malian children with hemoglobin C trait have reduced serorecognition of variant surface antigens compared to wild type children, suggesting that abnormally expressed variant surface antigens limit the antibody response. We hypothesize that a primary protective mechanism against malaria in children with Hemoglobin C trait is abnormal expression of a subset of parasite variant surface antigens. Identifying these abnormally expressed variant surface antigens may yield a subset of malaria proteins critical to disease pathogenesis. Using novel transcriptomic and proteogenomic techniques, we aim to identify the transcripts (Aim 1) and expressed variant surface antigens (Aim 2) in infections in children with hemoglobin AC, AA, and AS in a recent longitudinal study of malaria incidence in rural Mali. We will identify transcription and expression differences in variant surface antigens between these groups with respect to clinical and asymptomatic malaria episodes. We will then measure how seroreactivity changes to these variant surface antigens following a symptomatic versus an asymptomatic infection in these groups (Aim 3) with a custom protein microarray so that we can link disease vulnerability with variant surface antigen expression. The contributions of our research will be to identify variant surface antigen transcripts in symptomatic and asymptomatic infections of Malian children with hemoglobin AC, AA, and AS; variant surface antigens present on the surface of infected erythrocytes in these infections; and differences in seroreactivity to variant surface antigens. Our approach will determine if the effects of hemoglobin C trait occur during transcription or protein expression and translocation to the erythrocyte surface. Our ultimate goal is to identify a subset of variant surface antigen epitopes for a malaria vaccine to protect against clinical disease. Upon completion, we will be prepared to precisely map and define epitopes underlying natural protection to clinical malaria for the variant surface antigens identified as critical to disease pathogenesis and hemoglobin C trait protection.

Public Health Relevance

Malian children with Hemoglobin C trait have fewer malaria episodes than their peers do. This project uses transcriptome sequencing, protein identification techniques, and a custom protein microarray to identify malaria surface proteins on infected erythrocytes that may be critical to causing disease and abnormally expressed in children with Hemoglobin C. This will provide insight into how malaria parasites cause disease in children in sub-Saharan Africa and define a subset of these malaria surface proteins that may be a promising vaccine target.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL146377-01
Application #
9709682
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Qasba, Pankaj
Project Start
2019-07-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201