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Abstract
Plasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. Antibodies to particular non-CD36-binding PfEMP1s are associated with protection against severe disease. We hypothesized that given lifelong P. falciparum exposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, particularly to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). Using a protein microarray, we determined serologic responses to 166 reference PfEMP1 fragments during a dry and subsequent malaria transmission season in Malian adults. Malian adult sera had PfEMP1 serologic responses throughout the year, with decreased reactivity to a small subset of PfEMP1 fragments during the dry season and increases in reactivity to a different subset of PfEMP1 fragments during the subsequent peak malaria transmission season, especially for intracellular PfEMP1 domains. For some individuals, PfEMP1 serologic responses increased after the dry season, suggesting antigenic switching during asymptomatic infection. Adults were more likely to experience variable serorecognition of CD36-binding PfEMP1s than non-CD36-binding PfEMP1s that bind EPCR or ICAM-1, which remained serorecognized throughout the year. Sustained seroreactivity to non-CD36-binding PfEMP1s throughout adulthood amid seasonal fluctuation patterns may reflect underlying protective severe malaria immunity and merits further investigation.
Highlights
Plasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium
PfEMP1s binding CD36 via CIDRα2 domains have been associated with uncomplicated or asymptomatic malaria[18,19], whereas PfEMP1s binding the endothelial protein C receptor (EPCR)[20] via CIDRα1 domains and PfEMP1s binding the intercellular adhesion molecule-1 (ICAM-1) via DBLβ domains have been associated with severe m alaria[21,22,23,24,25,26,27]
Malian adults maintained broad serorecognition of PfEMP1s across the year, including the vast majority of extracellular and intracellular PfEMP1 fragments pre-dry season (92.8% and 86.4%, respectively), pre-malaria transmission season (94.2% and 95.5%, respectively), and post-malaria transmission season (95.7% and 95.5%, respectively)
Summary
Plasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. We hypothesized that given lifelong P. falciparum exposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). In regions with high malaria transmission, children under five years of age are most vulnerable to severe Plasmodium falciparum disease[1] Older children in these areas acquire immunity to clinical malaria[1], leading to predominantly asymptomatic malaria infections in adulthood. Non-sterile natural immunity to malaria is incompletely understood, acquiring antibodies to variant surface antigens (VSA)—proteins expressed on the infected red blood cell surface—plays an important role. We hypothesized that adults with lifelong exposure to P. falciparum acquire serorecognition of most PfEMP1 antigens and maintain significant PfEMP1 antibody responses throughout the year, to non-CD36-binding PfEMP1s, reflecting sustained protection against severe disease. We predicted that PfEMP1 serologic responses decrease during the dry season and increase during the malaria transmission season due to the intense, seasonal nature of parasite exposure in Mali
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