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  [1].

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 [2].

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 [3]. 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 [4]–[6].

Among all these receptors, CR1 (named also CD35) plays a key role in the control of complement system* activation and the immune clearance** [7].

Indeed, it favours the RBC invasion by P. falciparum [8], [9], and is involved in the rosetting processes [10].

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) [11].

The McCa antigen is a high-frequency antigen while the antigens Sl2 and McCb are only represented at high frequency in African populations [12]–[21].

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 [10].

Nevertheless, epidemiological data supporting this possibility are contradictory, with some studies showing an association between Sl and McC genotypes and severe malaria[12], [20], [22], and others finding none [13], [19], [23]–[26].

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 [27]–[31] 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 [32]. 
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.

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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 [30], [33]–[36].

Moreover, although it remains challenging, it would be interesting to lead these same epidemiological and functional studies within a single population.

Thanks for reading.

And don’t forget: Fight Malaria

Notes

*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.

Bibliography:

[1]    World Health Organisation (WHO), World Malaria Report 2017. 2017.

[2]    A. Trampuz, M. Jereb, I. Muzlovic, and R. M. Prabhu, “Clinical review: Severe malaria.,” Crit. Care, vol. 7, no. 4, pp. 315–23, Aug. 2003.

[3]    N. Day and A. M. Dondorp, “The Management of Patients with Severe Malaria,” 2007.

[4]    N. Rasti, M. Wahlgren, and Q. Chen, “Molecular aspects of malaria pathogenesis,” FEMS Immunol. Med. Microbiol., vol. 41, no. 1, pp. 9–26, May 2004.

[5]    A. Craig and A. Scherf, “Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion.,” Mol. Biochem. Parasitol., vol. 115, no. 2, pp. 129–43, Jul. 2001.

[6]    L. Turner et al., “Severe malaria is associated with parasite binding to endothelial protein C receptor,” Nature, vol. 498, no. 7455, pp. 502–505, Jun. 2013.

[7]    M. Krych-Goldberg and J. P. Atkinson, “Structure-function relationships of complement receptor type 1.,” Immunol. Rev., vol. 180, pp. 112–22, Apr. 2001.

[8]    C. Spadafora et al., “Complement Receptor 1 Is a Sialic Acid-Independent Erythrocyte Receptor of Plasmodium falciparum,” PLoS Pathog., vol. 6, no. 6, p. e1000968, Jun. 2010.

[9]    W.-H. Tham et al., “Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand,” Proc. Natl. Acad. Sci., vol. 107, no. 40, pp. 17327–17332, Oct. 2010.

[10]    J. A. Rowe, J. M. Moulds, C. I. Newbold, and L. H. Miller, “P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1,” Nature, vol. 388, no. 6639, pp. 292–295, Jul. 1997.

[11]    J. M. Moulds, “The Knops blood-group system: a review.,” Immunohematology, vol. 26, no. 1, pp. 2–7, 2010.

[12]    V. Thathy, J. M. Moulds, B. Guyah, W. Otieno, and J. A. Stoute, “Complement receptor 1 polymorphisms associated with resistance to severe malaria in Kenya.,” Malar. J., vol. 4, p. 54, Nov. 2005.

[13]    P. A. Zimmerman et al., “CR1 Knops blood group alleles are not associated with severe malaria in the Gambia.,” Genes Immun., vol. 4, no. 5, pp. 368–73, Jul. 2003.

[14]    J. M. Moulds et al., “Identification of the Kna/Knb polymorphism and a method for Knops genotyping.,” Transfusion, vol. 44, no. 2, pp. 164–9, Feb. 2004.

[15]    J. Fitness et al., “Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi.,” Am. J. Trop. Med. Hyg., vol. 71, no. 3, pp. 330–40, Sep. 2004.

[16]    D. T. Covas, F. S. de Oliveira, E. S. Rodrigues, K. Abe-Sandes, W. A. Silva, and A. M. Fontes, “Knops blood group haplotypes among distinct Brazilian populations,” Transfusion, vol. 47, no. 1, pp. 147–153, Jan. 2007.

[17]    M. Gandhi, A. Singh, V. Dev, T. Adak, A. P. Dashd, and H. Joshi, “Role of CR1 Knops polymorphism in the pathophysiology of malaria: Indian scenario.,” J. Vector Borne Dis., vol. 46, no. 4, pp. 288–94, Dec. 2009.

[18]    J. H. Yoon et al., “The polymorphism of Knops blood group system in Korean population and their relationship with HLA system,” Hum. Immunol., vol. 74, no. 2, pp. 196–198, Feb. 2013.

[19]    H. H. Hansson et al., “Human genetic polymorphisms in the Knops blood group are not associated with a protective advantage against Plasmodium falciparum malaria in Southern Ghana,” Malar. J., vol. 12, no. 1, p. 400, Nov. 2013.

[20]    S. M. Kariuki et al., “The genetic risk of acute seizures in African children with falciparum malaria,” Epilepsia, vol. 54, no. 6, pp. 990–1001, Jun. 2013.

[21]    N. A. Eid et al., “Candidate malaria susceptibility/protective SNPs in hospital and population-based studies: the effect of sub-structuring.,” Malar. J., vol. 9, p. 119, May 2010.

[22]    R. Tettey, P. Ayeh-Kumi, P. Tettey, G. O. Adjei, R. H. Asmah, and D. Dodoo, “Severity of malaria in relation to a complement receptor 1 polymorphism: a case-control study.,” Pathog. Glob. Health, vol. 109, no. 5, pp. 247–52, Jul. 2015.

[23]    M. Jallow et al., “Genome-wide and fine-resolution association analysis of malaria in West Africa,” Nat. Genet., vol. 41, no. 6, pp. 657–665, Jun. 2009.

[24]    A. Manjurano et al., “Candidate human genetic polymorphisms and severe malaria in a Tanzanian population.,” PLoS One, vol. 7, no. 10, p. e47463, 2012.

[25]    O. Toure et al., “Candidate Polymorphisms and Severe Malaria in a Malian Population,” PLoS One, vol. 7, no. 9, p. e43987, Sep. 2012.

[26]    K. A. Rockett et al., “Reappraisal of known malaria resistance loci in a large multicenter study,” Nat. Genet., vol. 46, no. 11, pp. 1197–1204, Nov. 2014.

[27]    A. C. ALLISON, “Protection afforded by sickle-cell trait against subtertian malareal infection.,” Br. Med. J., vol. 1, no. 4857, pp. 290–4, Feb. 1954.

[28]    J. May et al., “Hemoglobin Variants and Disease Manifestations in Severe Falciparum Malaria,” JAMA, vol. 297, no. 20, p. 2220, May 2007.

[29]    T. N. Williams et al., “Sickle Cell Trait and the Risk of Plasmodium falciparum Malaria and Other Childhood Diseases,” J. Infect. Dis., vol. 192, no. 1, pp. 178–186, Jul. 2005.

[30]    F. J. I. Fowkes, S. J. Allen, A. Allen, M. P. Alpers, D. J. Weatherall, and K. P. Day, “Increased Microerythrocyte Count in Homozygous α+-Thalassaemia Contributes to Protection against Severe Malarial Anaemia,” PLoS Med., vol. 5, no. 3, p. e56, Mar. 2008.

[31]    S. H. Atkison et al., “Epistasis between the haptoglobin common variant and α + thalassemia influences risk of severe malaria in Kenyan children,” Blood, vol. 123, no. 13, pp. 2008–2016, Mar. 2014.

[32]    D. H. Opi et al., “Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia,” Elife, vol. 7, Apr. 2018.

[33]    J. Carlson, G. B. Nash, V. Gabutti, F. al-Yaman, and M. Wahlgren, “Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation.,” Blood, vol. 84, no. 11, pp. 3909–14, Dec. 1994.

[34]    M. A. Krause et al., “α-Thalassemia Impairs the Cytoadherence of Plasmodium falciparum-Infected Erythrocytes,” PLoS One, vol. 7, no. 5, p. e37214, May 2012.

[35]    D. H. Opi et al., “Mechanistic Studies of the Negative Epistatic Malaria-protective Interaction Between Sickle Cell Trait and α+thalassemia.,” EBioMedicine, vol. 1, no. 1, pp. 29–36, Nov. 2014.

[36]    D. H. Opi, S. Uyoga, E. N. Orori, T. N. Williams, and J. A. Rowe, “Red blood cell complement receptor one level varies with Knops blood group, α+thalassaemia and age among Kenyan children,” Genes Immun., vol. 17, no. 3, pp. 171–178, Apr. 2016.

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