A Role for Fetal Hemoglobin and Maternal Immune IgG in Infant Resistance to Plasmodium falciparum Malaria

Chanaki Amaratunga,Tatiana M Lopera-Mesa,Takayuki Arie,Hisashi Fujioka,Nathaniel J Brittain,Jeffrey R Keefer,Rick M Fairhurst,Rushina Cholera,Anne Charlotte Gruner

doi:10.1371/journal.pone.0014798

Abstract

BackgroundIn Africa, infant susceptibility to Plasmodium falciparum malaria increases substantially as fetal hemoglobin (HbF) and maternal immune IgG disappear from circulation. During the first few months of life, however, resistance to malaria is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease. This resistance has previously been attributed in part to poor parasite growth in HbF-containing red blood cells (RBCs). A specific role for maternal immune IgG in infant resistance to malaria has been hypothesized but not yet identified.Methods and FindingsWe found that P. falciparum parasites invade and develop normally in fetal (cord blood, CB) RBCs, which contain up to 95% HbF. However, these parasitized CB RBCs are impaired in their binding to human microvascular endothelial cells (MVECs), monocytes, and nonparasitized RBCs – cytoadherence interactions that have been implicated in the development of high parasite densities and the symptoms of malaria. Abnormal display of the parasite's cytoadherence antigen P. falciparum erythrocyte membrane protein-1 (PfEMP-1) on CB RBCs accounts for these findings and is reminiscent of that on HbC and HbS RBCs. IgG purified from the plasma of immune Malian adults almost completely abolishes the adherence of parasitized CB RBCs to MVECs.ConclusionsOur data suggest a model of malaria protection in which HbF and maternal IgG act cooperatively to impair the cytoadherence of parasitized RBCs in the first few months of life. In highly malarious areas of Africa, an infant's contemporaneous expression of HbC or HbS and development of an immune IgG repertoire may effectively reconstitute the waning protective effects of HbF and maternal immune IgG, thereby extending the malaria resistance of infancy into early childhood.

Highlights

In Africa, resistance to Plasmodium falciparum malaria in the first few months of life is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease [1]
Our data suggest a model of malaria protection in which HbF and maternal IgG act cooperatively to impair the cytoadherence of parasitized red blood cells (RBCs) in the first few months of life
We found that HbF impairs the binding of parasitized RBCs to human microvascular endothelial cells (MVECs), monocytes, and nonparasitized erythrocytes – cytoadherence interactions that contribute to the development of high parasite densities and the symptoms of malaria

Summary

Introduction

In Africa, resistance to Plasmodium falciparum malaria in the first few months of life is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease [1]. Infant resistance to malaria has previously been attributed to poor parasite growth in HbF-containing RBCs. While several studies have established that P. falciparum parasites readily invade cord blood (CB) RBCs [4,5,6], the presence of HbF in three RBC types (CB, infant, and adult hereditary persistence of fetal hemoglobin, HPFH) was believed to restrict parasite growth [4,5,6,7]. During the first few months of life, resistance to malaria is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease This resistance has previously been attributed in part to poor parasite growth in HbF-containing red blood cells (RBCs). A specific role for maternal immune IgG in infant resistance to malaria has been hypothesized but not yet identified

Methods

Results

Conclusion