Blood groups and malaria: fresh insights into pathogenesis and identification of targets for intervention

Abstract

Purpose of review: This review summarizes recent advances in our understanding of the interaction between malaria parasites and blood group antigens and discusses how the knowledge gleaned can be used to target the development of new antimalarial treatments and vaccines.

Recent findings: Studies of the interaction between Plasmodium vivax and the Duffy antigen provide the clearest example of the potential for basic research on blood groups and malaria to be translated into a vaccine that could have a major impact on global health. Progress is also being made in understanding the effects of other blood group antigens on malaria. After years of controversy, the effect of ABO blood groups on falciparum malaria has been clarified, with the non-O blood groups emerging as significant risk factors for life-threatening malaria, through the mechanism of enhanced rosette formation. The Knops blood group system may also influence malaria susceptibility, although conflicting results from different countries mean that further research is required. Unanswered questions remain about the interactions between malaria parasites and other blood group antigens, including the Gerbich, MNS and Rhesus systems.

Summary: The interplay between malaria parasites and blood group antigens remains a fascinating subject with potential to contribute to the development of new interventions to reduce the global burden of malaria.

Figure 1. Life cycle of Plasmodium falciparum

When an infected female Anopheles mosquito takes a blood meal, sporozoite forms of Plasmodium falciparum are injected into the human skin. The sporozoites migrate into the bloodstream and then invade liver cells. The parasite grows and divides within liver cells for 8–10 days, then daughter cells, called merozoites, are released from the liver into the bloodstream, where they rapidly invade red blood cells (RBCs). Merozoites subsequently develop into ring, pigmented-trophozoite, and schizont stage parasites within the infected RBC. P. falciparum-infected erythrocytes express parasite-derived adhesion molecules on their surface, resulting in sequestration of pigmented-trophozoite and schizont stage-infected RBCs in the microvasculature. The asexual intraerythrocytic cycle lasts 48 h and is completed by the formation and release of new merozoites that will re-invade uninfected RBCs. It is during this asexual bloodstream cycle that the clinical symptoms of malaria (fever, chills, impaired consciousness, etc.) occur. During the asexual cycle, some of the infected RBCs develop into male and female sexual stages called gametocytes that are available to be taken up by feeding female mosquitoes. The gametocytes are fertilized and undergo further development in the mosquito, resulting in the presence of sporozoites in the mosquito’s salivary glands ready to infect another human host. Reproduced with permission from [1].

Figure 2. The role of Duffy antigen receptor for chemokines in Plasmodium vivax invasion

(a) The Plasmodium vivax Duffy binding protein (PvDBP) is located in the micronemes of the merozoite (green). After attachment of the merozoite to the red blood cell (RBC) (reticulocyte) surface, the merozoite re-orientates, so that its apical end is in contact with the RBC membrane. DBP is then released and a tight junction (blue) is formed between the merozoite and the RBC membrane. The tight junction moves from the apical to posterior pole as the merozoite invades the RBC, propelled by an actin-myosin motor. The RBC membrane is resealed once invasion is complete. The entire process from initial attachment to completed invasion takes approximately 1 min. (b) A model of the binding of the PvDBP to the Duffy antigen receptor for chemokines (DARC) [inset from (a)]. Amino acid residues in PvDBP that are conserved are green and polymorphic yellow. Antibodies are predicted to bind to a polymorphic region of the DBP that is separate from, but may overlap with, the DARC-binding site. Reproduced with permission from [15].

Figure 3. Plasmodium falciparum rosetting

(a) Rosetting in a Plasmodium falciparum in-vitro culture, observed after preparation of a Giemsa-stained thin smear and light microscopy. (b). Schematic representation of P. falciparum rosette formation in the microvasculature. Rosetting infected red blood cells (RBCs) are thought to have the ability to bind simultaneously to microvascular endothelial cells and uninfected RBCs, resulting in obstruction to blood flow in microvessels contributing to pathological effects such as hypoxia and acidosis. Adapted with permission from [1].