HbS Protection from P. falciparum Infection

Abstract

Recent investigations have highlighted various mechanisms of interaction between the Plasmodium falciparum (P. falciparum) parasite and the host, which are important for the understanding of the well-known protective effect by haemoglobinopathies like Sickle Cell Trait and α-Thalassemia against incidence and severity of malaria. Attention must therefore be given in the first place to the modifications induced in red blood cells (RBC) by the parasite in order to survive and display its pathogenic action: in this context, both the production of novel transport pathways able to support the development of the parasite during the erythrocytic cycle (in a cell which has lost transport activities during maturation process) and the changes induced to the RBC actin cyto-skeleton are discussed. As for the mechanisms involved in protection from P. falciparum infection, they can be of genetic, molecular, immunological character as well as interactive, due to the interplay of different factors. Some protection is afforded by genetic changes preventing P. falciparum to survive and proliferate within the red cell: such changes may include variants of the “basigin” receptor for the parasite antigens and inhibition by HbS of parasite-induced red cell remodelling. P. vivax infection may also be reduced in Duffy-negative heterozygotes. Genetic factors specifically interacting with the development of the infection are the sickle cell trait, the presence of foetal Haemoglobin (HbF), particularly in its pancellular distribution and genes associated with malaria resistance, identified by genome-wide linkage studies. Selective advantage of HbAS heterozygotes over HbS homozygotes in the clinical course of malaria can be explained by the so called “balanced polymorphism”. The presence of foetal haemoglobin (HbF) has also a protective effect, due to retardation of parasite growth in such situation: this is the rationale behind the attempts to reactivate HbF production in Sickle Cell Disease(SCD). Phagocytosis of infected red blood cells (RBC’s) has a significant protective effect by keeping a low level of parasitemia in HbAS subjects. Recent research also points to the role of modifications of RBC’s adherence to microvascular endothelium as an important factor in the pathogenesis of malaria and suggest that abnormal Hb’s like HbS and HbC as well as α-thalassemia can impair the adhesion of the parasite major ligand to host cells, thus limiting the sequestration of parasite –invaded red cells in many tissues and organs, like the brain. A special role in protection from malaria can be ascribed to molecular mediators, particularly a sequence involving haeme-oxygenase (HMO-1), which appears up-regulated in transgenic sickle cell mice: the action of HMO-1 prevents the cytotoxic effect of free heme and is in turn mediated by carbon monoxide, which inhibits Hb oxidation and further release of haeme from haemoglobin. Immunological factors are important, as shown by the development of children immunity to malaria, a rapid process in the early years of age (anti-disease immunity) and a slower one later (anti-parasite immunity); of remarkable interest are the antibodies to variant surface antigens (VSA) expressed by the parasite: an association was actually found between HbAS and the presence of IgG anti-VSA responses. Tolerance to parasite infection seems possible as the presence of β-chain mutations like in HbSAD mice provides a reduced incidence of experimental cerebral malaria. The possible role of various types of interferon is also under scrutiny. An example of interactions between different pathways comes from very recent studies, as it has been found that a mutation in the FAS gene promoter encoding the protein C- 95 results in a reduction of severe malaria incidence; as C-95 promotes apoptosis, an effect due to a C-95 – aided killing of immune cells, thus preventing an excessive immune response, is an interesting case of molecular-immunological interplay. Moreover, recent data on the mechanisms of malaria resistance, , show that during the intraerythrocytic life cycle of P. falciparum, two microRNA (miRNA),highly enriched in HbAS and HbSS erythrocytes, become integrated into the parasite messenger RNAs and cause translational inhibition, thus acting as negative regulators of parasite growth. It appears therefore that a very peculiar host defense strategy is working in sickle cell erythrocytes through miRNA activity.