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

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.

Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia

“…17 In contrast to these adverse effects, it is possible that hydroxyurea could have beneficial effects against malaria because HbF, which is increased by hydroxyurea, inhibits Plasmodium falciparum growth in vitro. 18 Hydroxyurea treatment also generates nitric oxide, 19 which protects against severe malaria in animals 20,21 and humans. 22 With these contrasting potential mechanisms, the risks and benefits of hydroxyurea in a malaria endemic setting remain unknown, and many critical questions remain regarding the safety, feasibility, and efficacy of hydroxyurea for children with SCA living in malaria-endemic settings within sub-Saharan Africa.…”

Human Genetic Contribution to the Outcome of Infection with Malaria Parasites

“…Age has often been used as a proxy for the acquisition of immunity and accounting for age should reduce the contribution of that arm of the immune system to the genetic effect. It should be noted, however, that there may be a genetic contribution to acquired immunity (Stirnadel et al, 1999) and there is now some evidence that the inherited blood disorders operate interactively with the acquired immune response (Amaratunga et al, 2011). Nevertheless, our analyses would suggest that there is a contribution to the genetic effect from the innate arm of the immune system.…”

Thalassemias Validate Germ Terrain Duality of Malaria

“…There is a need for competent scientists to create an index of the relative resistances of abnormal haemoglobins (obviously with HbS as the standard) to malaria so that we may come to a fuller understanding of the germ terrain duality of malaria-and hopefully of other diseases as well [11][12][13][14][15]. Normal haemoglobin (Hb A) provides no resistance to malaria [16].…”