Malaria is the most important human parasitic disease. In 2016, it affected in about 216 million individuals and was responsible for 445 000 deaths. Sub-Saharan Africa continues to support a disproportionate share of the global burden of malaria with 89% of cases and 91% of deaths, including a majority of children under five years old .
The disease is caused by an intra-erythrocytic Apicomplexa protozoa of Plasmodiidae family and Plasmodium genus. This parasite is transmitted by the bite of an infected female mosquito of Anopheles genus during a blood meal .
Five species can infect humans (P. falciparum, P. malariae, P. ovale, P. vivax, and P. knowlesi) but P. falciparum (Welsh, 1897) is the most widespread species infecting humans throughout the world and is the only one that may give rise to cerebral malaria, and it is responsible for nearly all malaria-associated deaths.
In most cases, the malaria infection by P. falciparum shows infectious symptoms similar to the flu with fever, chills and abdominal pains.
However, within some populations with risk factor associated (age, malnutrition or immune-depression) or not immunized against parasite (children under 5 years, pregnant women, travelers), the P. falciparum infection may give rise to severe malaria whose the most known clinical form is cerebral malaria reflected by convulsions, coma, fever and other symptoms such as respiratory distress.
From a physiopathological point of view, severe malaria would be associated with a sequestration of infected red blood cells (iRBCs) binding to endothelial cells of brain microvasculatures of the host (cytoadherence) or to the non-infected RBCs (rosetting) via protuberances located at the surface of iRBCs.
These phenomena obstruct the bloodstream, causing the reduction of blood perfusion into organs . They depend on molecular host-parasite interactions between parasitic antigens and specific receptors of endothelial cells which are expressed at the surface of RBCs.
Among the parasitic antigens, P. falciparum erythrocyte membrane protein 1 (PfEMP1) seems to play a key role, interacting with host-receptors such as the heparan sulfate (HS) and chondroitin sulfate (CSA) involved in the gestational malaria, but also the complement-receptor-1(CR1), the antigen of the ABO blood group as well as the non-immune immunoglobuline (Ig) which seems implied in the rosetting phenomenon, ICAM-1 and the endothelial protein C receptor (EPCR) which would be potentially involved in the cerebral malaria of children under 5 years in Sub-Saharan Africa –.
Among all these receptors, CR1 (named also CD35) plays a key role in the control of complement system* activation and the immune clearance** .
Indeed, it favours the RBC invasion by P. falciparum , , and is involved in the rosetting processes .
Mutations of CR1 form the basis of the Knops blood group system of antigens, that including 3 antithetical antigen pairs: Kna/Knb (Knops), McCa/McCb (McCoy) and Sl1/Sl2 (Swain-Langley 1 et 2) .
The McCa antigen is a high-frequency antigen while the antigens Sl2 and McCb are only represented at high frequency in African populations –.
At the end of 90’s, a study showed that RBCs from donors with these mutations of CR1 bind poorly to the PfEMP1 that mediates the rosetting by iRBCs, potentially protecting against severe malaria by reducing resetting .
Nevertheless, epidemiological data supporting this possibility are contradictory, with some studies showing an association between Sl and McC genotypes and severe malaria, , , and others finding none , , –.
Moreover, several studies showed that hemoglobinopathies such as the sickle cell anaemia and the thalassaemia which are prevalent genetic diseases in Africa and in Mediterranean countries would protect against severe malaria – in the malaria-endemic areas.
In order to clarify the relationship between each allele (Sl and McC) and the severe malaria, the team of Prof JA Rowe from the University of Edinburgh (Scotland) in collaboration with the University of Oxford and Malian and Kenyan research institutes, did an epidemiological study of case-control on 5545 Kenyan children suffering of cerebral malaria . Results showed an opposing effect for these 2 alleles.
Indeed, statistical models showed that the mutation Sl2 would be associated with a significant protection against severe malaria and death in these Kenyan children.
However, the mutation McCb would be associated with a higher susceptibility to severe malaria with an increase of death by cerebral malaria in these Kenyan children.
Meanwhile, the team led another cohort study on 208 Kenyan children suffering from uncomplicated malaria or common non-malarial childhood diseases such as gastroenteritis, in order to examine the associations of these 2 alleles with these infections.
Results showed that Sl2 would protect against uncomplicated malaria while McCb would protect against different common childhood diseases such as gastroenteritis and respiratory diseases.
Unexpectedly, researchers observed a significant interaction between Sl2 and α+thalassaemia genotype, such that these protective associations were only seen in individuals of normal α-globin, whatever the type of malaria infection (uncomplicated or severe). This suggests an influence of the α+thalassaemia on these protective associations, a result reminding interaction that has been observed between α+thalassaemia and other malaria-protective mutations such as the one conferring the sickle cell anaemia.
Therefore, it suggests that α+thalassaemia could have a broad effect on multiple malaria-protective mutations, concluding to the discrepant outcomes of previous association studies.
Finally, researchers did a small case-control study on 167 P. falciparum isolates from Malian children suffering from malaria, in order to investigate the influence of these alleles on the formation of parasitic rosettes, as a potential functional explanation for their results. Results showed that the rosette frequency was significantly lower in P. falciparum isolates from malaria patients with one or more Sl2 alleles than in isolates from Sl1/Sl1 donors, whereas McC genotype had no significant associations with P. falciparum rosette frequency suggesting that Sl2 could prevent the rosette formation involved in severe malaria and therefore, could explain the protective association of Sl2 against cerebral malaria.
To date, this publication is the most fully completed showing the protective association between Sl2 and the malaria infection, whether cerebral or uncomplicated and describing the interaction between Sl2 and α+thalassaemia,
However, further studies are necessary to study these interactions and discover the mechanism of protection afforded by α+thalassaemia which remains controversial , –.
Moreover, although it remains challenging, it would be interesting to lead these same epidemiological and functional studies within a single population.
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*complement system: Part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promotes inflammation, and attacks the pathogen’s cell membrane.
** immune clearance: Accelerated removal of an antigen from the bloodstream that follows the initiation of an antibody response by the immune system.
 World Health Organisation (WHO), World Malaria Report 2017. 2017.
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