INTRODUCTION — Most red cell genetic defects in human populations (eg, thalassemia, G6PD deficiency, sickle cell anemia) appear to be due to the exposure to malaria, a disease estimated to have arisen approximately 3000 years ago with the emergence of agriculture [1-3]. Human malaria appears to have followed the zoonotic acquisition of malaria infections from primates [4]. Humans exhibit variable susceptibility to malarial infection; most of the resistance to this infection is either genetic, environmental, based upon previous exposure, or access to therapy.
A study of the relative importance of each of these factors to the overall burden of malarial disease in human populations was examined in Sri Lanka. Longitudinal studies showed that 20 percent of the variation in the intensity of disease was explained by repeatable differences between patients and approximately half was attributable to host genetics [5]. A similar analysis in Africa demonstrated 25 percent of the total variation in the incidence of hospital admission for malaria was explained by additively-acting host genes, with 2 percent of this variation due to presence of the sickle cell trait [6].
The role of certain blood group antigens in malarial infection and genetic resistance to malaria associated with abnormalities in the red cell cytoskeleton will be reviewed here. The overall subject of anemia in malaria, as well as malarial resistance associated with the hemoglobinopathies (eg, hemoglobins S, C, E, thalassemia), are discussed separately. (See "Anemia in malaria" and "Protection against malaria in the hemoglobinopathies".)
Development of a malaria vaccine based upon various malarial antigens and/or their receptors is discussed separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Vaccination'.)
MECHANISMS OF PROTECTION — Plasmodium falciparum malaria, the most deadly form of malaria, has a life cycle that includes a sexual cycle in an Anopheles mosquito and a human cycle that includes a liver stage and an obligatory erythrocytic stage. Genetic resistance is much better defined for the erythrocytic stage and may involve one or more of the following mechanisms:
●Inhibition of merozoite entry into the red cell
●Impairment of intracellular parasite growth
●Prevention of the erythrocyte lysis that occurs with parasite maturation, leading to release of merozoites into the bloodstream
Malarial invasion of the red cell is a complex process, involving initial nonspecific attachment, reorientation of the polarity of the merozoite, red cell membrane flapping, and the zipper-type introjection of the merozoite into the red cell [7,8]. It is therefore not surprising that mutations involving the red cell membrane (eg, surface antigens and cytoskeletal proteins) could interfere with such invasion.
As will be described below, malarial invasion of the red cells requires both red cell receptors, such as the Duffy blood group antigen for Plasmodium vivax and glycophorin A for P. falciparum, and parasite proteins that bind to the receptor [2,9-11].
RED CELL SURFACE ANTIGENS — Red cell surface antigens can affect the likelihood of developing malaria. The best described are the Duffy blood group determinants and the glycophorins, although there is increasing evidence for the role of the ABO blood group system.
Duffy blood group system — The Duffy blood group system is polymorphic and includes five antigens, two of which are codominant alleles (Fya and Fyb) that differ by a change at nucleotide 306: guanine in Fya and adenine in Fyb [12]. Both Fya and Fyb reside in a glycoprotein of approximately 40 kD, known as the Duffy antigen receptor for chemokines (DARC, CD234), which acts as a receptor for certain pro-inflammatory cytokines (eg, IL-8, monocyte chemotactic protein-1, RANTES) [13,14]. (See "Red blood cell antigens and antibodies", section on 'Duffy blood group system'.)
Duffy antigen negativity corresponds to a null genotype in which neither the Fya nor Fyb antigen (Fy(a-b-)) is expressed. Most Duffy-negative people of African descent have a silent Fyb allele with a single nucleotide substitution that impairs promoter activity in erythroid cells [15]. The percent of the population with the Fy(a-b-) phenotype reaches 100 percent in much of Sub-Saharan Africa. It seems that its selective advantage (ie, resistance to invasion by the merozoites of P. vivax) has driven this phenotype nearly to fixation. In Gambian individuals, for example, 100 percent are Duffy negative [16]. This trait is also seen in many other populations [17,18].
Fy(a-b-) erythrocytes were first shown to be resistant to invasion by the merozoites of the monkey or simian parasite, Plasmodium knowlesi, which is similar to P. vivax [19]. The importance of the Duffy blood group system in P. vivax infection and other malaria infections in man has been shown in several ways:
●In a 1958 study performed before in vitro malaria cultures were available, human volunteers were exposed to mosquitoes infected with P. vivax [20]. Duffy-negative individuals were resistant to infection, while controls developed malaria 11 to 15 days after exposure.
●The crucial role of the Duffy blood group antigen for erythrocyte invasion was obtained in epidemiologic studies of soldiers with P. vivax infection acquired in Vietnam [21] and in children with malaria in Papua New Guinea [18].
●Using a short-term in vitro culture system, antibodies directed against a new Duffy determinant, Fy6, blocked invasion of erythrocytes by P. vivax as effectively as antibodies directed against the intact molecule [22].
●The Duffy blood group antigen is a receptor for IL-8 and melanoma growth stimulatory activity (MGSA); invasion of P. knowlesi blood stage merozoites into erythrocytes carrying the Duffy antigen can be inhibited by MGSA and IL-8 [23]. Subsequent studies narrowed the binding site on the Duffy antigen to a 35 amino acid region [24].
●P. vivax infections in Duffy-negative individuals have been described across countries in Africa, South American, and Asia, with marked heterogeneity by region in the odds of P.vivax infection among Duffy-negative individuals [25].
●The Duffy Fy(a) allele, compared with the Duffy Fy(b) allele, significantly diminishes binding of Pv Duffy binding protein (PvDBP) at the erythrocyte surface, and is associated with a reduced risk of clinical P. vivax infection in humans [26].
●Platelet factor-4 (PF-4) released during platelet activation has been implicated in the killing of parasites within red blood cells. PF-4 appears to bind to infected red blood cells by the Duffy antigen. These in vitro phenomena suggest somewhat paradoxically that Duffy negative individuals would be at a disadvantage when infected with P. falciparum malaria [27]. The role of this pathway of parasite killing in patients with malaria remains to be determined.
Parasite proteins that bind to Duffy antigen — One protein from P. vivax and three proteins from the simian malaria P. knowlesi bind to the Duffy blood group antigen [28]. These proteins share sequence homology and a cysteine-rich domain was found within P. vivax Duffy binding protein (PvDBP), which mediates adhesion to Duffy blood group-positive but not Duffy blood group-negative human erythrocytes. The homologous domain of the proteins from P. knowlesi also bound erythrocytes but had different specificities [9].
The erythrocyte binding domains in these proteins, namely the Duffy binding domains, also showed sequence conservation with the domain for erythrocyte binding in the P. falciparum protein, erythrocyte-binding antigen-175, which bound to sialic acid on human erythrocytes [10,11]. The conserved binding domain between distant malarial species strongly suggests that these structures are functionally significant and might therefore be potential vaccine candidates.
These suggestions are consistent with hyper-variability of the erythrocyte-binding domain in the P. vivax Duffy-binding protein [29]. The binding domains within these PvDBPs lie within a conserved N-terminal cysteine-rich region of 330 amino acids [30,31]. Recombinant proteins have been developed that stimulate blocking antibodies and block erythrocyte invasion [32]. There is considerable natural variation in the sequence of the binding domains in PvDBPs, and multiple alleles of this parasite protein are being tested to induce strain-transcending immunity [33]. However, human vaccination with P. vivax Duffy-binding protein region II (Salvador strain), using a prime-boost strategy, appears to induce strain-transcending antibodies [34].
It is encouraging that a broadly neutralizing human monoclonal antibody that inhibited invasion of all tested strains of P. vivax can be isolated from volunteers vaccinated with P. vivax Duffy-binding protein [35]. Other groups have identified a highly conserved binding-inhibitory epitope in P. vivax Duffy-binding protein region II that could form a component of a broadly inhibitory, strain-transcending subunit vaccine [36]. Vaccine development is discussed in more detail separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Vaccination'.)
Glycophorin A and other surface antigens — Malarial parasites use several receptors on the surface of erythrocytes during invasion and during the rosetting of unaffected erythrocytes by infected erythrocytes. The glycophorins act as receptors for several malarial ligands [37]. Engagement of glycophorins may change red blood cell deformability to permit red blood cell invasion [38]. However, epidemiologic and laboratory evidence for significant protection against P. falciparum malaria by specific blood group polymorphisms is limited.
The capacity of malarial parasites to invade cells with modified O-linked saccharides is reduced. As examples:
●Removal of sialic acid (N-acetyl neuraminic acid) from the red cell surface reduces invasion [39-42].
●Tn+ erythrocytes (constitutively deficient in sialic acid and galactose in O-linked oligosaccharides) and Cad+ erythrocytes (with an extra N-acetyl galactosamine residue next to sialic acid residues) are resistant to invasion [43-45].
However, there is no evidence that the blood groups Tn+, Cad+ or En- (sialic acid deficient) or other variants of glycophorin A reach polymorphic frequencies in those living in endemic areas for malaria. This was somewhat puzzling as a malarial ligand for glycophorin A has been identified (EBA-175), and monoclonal antibodies to glycophorin A inhibit invasion of P. falciparum and P. knowlesi in vitro, while antibodies against glycophorin B, Rh, and Kell determinants have no effect [11,46].
A novel malaria resistance locus was reported close to the cluster of genes encoding glycophorins, and the MalGen consortium found that a haplotype at this locus provides 33 percent protection against severe malaria (odds ratio [OR] 0.67; 95% CI 0.60-0.76) [47].
The protective allele was not obvious, and a series of genetic analyses has demonstrated complex copy number variants (CNVs) at this locus. Genome sequencing was used to define reference sequences that allowed CNVs to be determined in over 3000 individuals [48]. Eight deletions and eight duplications were found, as well as 11 singleton variants in the glycophorin region. The combined allele frequency of glycophorin CNVs in African populations was 11 percent compared with 1.1 percent in non-African populations. One of the imputed CNVs, DUP4, is associated with decreased risk of severe malaria (OR 0.60; 95% CI 0.50-0.72), reducing the risk of both cerebral malaria and severe malarial anemia. The copy number profile of DUP4 is complex, and the gene encodes a protein where the extracellular domain of GYPB joins the transmembrane and intracellular domains of GYPA, creating a peptide sequence at their junction that is characteristic of the Dantu antigen in the MNS blood group system. Further family studies confirmed the identification of DUP4 as the variant encoding the Dantu+ (NE type) blood group phenotype. A single study reports parasite growth to be impaired in Dantu+ cells, consistent with the genetic epidemiology that the DUP4 variant encoding the Dantu NE blood group antigen is associated with protection from malaria [48,49]. An investigation of mechanisms underlying parasite resistance in individuals with the Dantu blood group suggests that increased red cell membrane tension limits malaria parasite invasion [50].
ABO(H) blood group system — Two studies have suggested that group A red cells are associated with severe malaria [51,52] while two additional studies, including a large study of 9000 children, have shown conclusively that blood group O confers protection (OR 1.2; 95% CI 1.09-1.32) [53-55]. (See "Red blood cell antigens and antibodies", section on 'ABO blood group system'.)
These observations are consistent with the low frequency of blood group A in many endemic malarial areas. Possible mechanisms for such a protective effect include the modulation of rosetting of uninfected red blood cells by infected red blood cells as well as the adherence of infected red blood cells to host receptors on monocytes, platelets, and endothelium [54]. This effect has been exhibited by some P. falciparum strains via the ABO group of red blood cells ex vivo and ABO blood group substances in vitro [56,57].
Clinical evidence from Thailand and East Africa has supported the role for the influence of rosetting by ABO blood group type. In these studies the frequency of rosetting parasites was less in blood isolated from Group O patients than from patients with Groups A and B [58] or A and AB [59,60]. The association of blood group O with protection and with reduced rosetting has also been confirmed in a large case control study of malaria [61]. It has been suggested that during exchange transfusion for resistant P. falciparum, it may be appropriate to consider the ABO blood of the transfused cells in treatment planning [62].
ABO blood group polymorphisms also modulate sialic acid recognition by some pathogen receptors [63], and may alter the rate of phagocytosis of infected red blood cells [64]; it remains unclear if these phenomena are mechanisms of protection in malaria [63].
Glycophorin B — There is experimental evidence that S-s-U- cells deficient in glycophorin B are relatively resistant to malarial invasion. There is also wide variation in the expression level of glycophorin B, which may be associated with variable susceptibility to malaria [65].
As an example, invasion of two different malarial strains was evaluated in erythrocytes that lack glycophorins A and B; the efficiency of invasion was 20 and 50 percent of normal, respectively [66]. Nevertheless, the blood group S-s-U- is found in 2 to 5 percent of Africans, suggesting malaria may have provided a selective force for this polymorphism [67]. The parasite ligand for glycophorin B has been identified as the P. falciparum Erythrocyte Binding Ligand-1 (EBL-1) [68].
Glycophorin C and the Gerbich antigen — A parasite receptor has been identified for the polymorphic glycophorin C that determines the Gerbich (Ge) blood group system. Deletion of exon 3 in the glycophorin C gene reaches a high frequency (46.5 percent) in coastal areas of Papua New Guinea where malaria is hyperendemic. The receptor for P. falciparum erythrocyte-binding antigen 140 (EBA-140, BAEBL) is glycophorin C; this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes [69]. EBA-140 is one of four P. falciparum invasion proteins with Duffy-binding like domains (DBLs) and the BAEBL allele containing threonine at position 121 (T121) (VSTK) can bind to glycophorin C [70].
In other reports, a normal protein 4.1/glycophorin C/p55 complex appears to be important for P. falciparum invasion and development [71-73]. The 4.1 protein is also involved in the binding to the red cell cytoskeleton of P. falciparum erythrocyte membrane protein-1 (PfEMP1), a protein involved in adhesion of malaria-infected red cells to the vascular endothelium [74,75]. (See 'Hereditary elliptocytosis' below.)
In a survey of 266 Melanesian individuals, the prevalence of P. falciparum and/or P. vivax infection was significantly lower in Gerbich-negative compared with Gerbich-positive individuals (5.7 versus 18.6 percent), while Plasmodium malariae occurred at comparable rates of approximately 8 percent in Gerbich-negative and Gerbich-positive individuals [76]. However, other studies have not shown that glycophorin C deficiency is associated with differences in either P. falciparum or P vivax infection [77]. While these findings suggest that Ge negativity has arisen in Melanesian populations by reducing severe malaria, confirmation by further case-control studies is awaited with interest.
Complement receptor type 1 and Knops blood group — The complement receptor type 1 (CR1) has been implicated in rosetting of uninfected red blood cells to P. falciparum-infected cells, a phenomenon which is associated with severe malaria [78]. CR1 has also been identified as the sialic acid-independent receptor used by parasites during the invasion of red blood cells by P. falciparum [79]; CR1 may also be a receptor during invasion by P. vivax merozoites [80]. The P. falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) at the complement control protein modules 1 to 3 (CCP1-3) at the membrane-distal amino terminus of CR1 that also bind to C4b and C3b [81].
The Knops blood group (KN) is located on CR1 and two of these antigens [ie, McCoy (McC) and Swain-Langley (Sl(a))], have been associated with mutations of CR1 [82]. The African alleles Sl(2) and McC(b) of CR1 are associated with the outcome of P. falciparum malaria. As an example, children with the Sl(2/2) genotype were less likely to have cerebral malaria (OR 0.17; 95% CI 0.04-0.72) than children with Sl(1/1) [83]. A Ghanaian study has shown McCa/b was associated with increased susceptibility to severe malaria (OR = 2.31; 95% CI 1.03-5.20, p = 0.043) and the McCb/b phenotype was associated with an 88 percent reduced risk of severe malaria (OR = 0.12; 95% CI 0.02-0.64, p = 0.013) [84]. A large case-control study of severe malaria in Kenyan children, adjusting for confounding factors, showed opposing associations of CR1 polymorphisms and malaria. The Sl2 polymorphism was associated with reduced odds of cerebral malaria and death, while the McCb polymorphism was associated with increased odds of cerebral malaria. Furthermore, the protective association of Sl2 was greatest in children with normal α-globin [85]. These complex associations may explain some previous studies that did not shown an association of CR1 alleles with protection from malaria [86].
Basigin — The Ok blood group antigen, basigin, has been identified as a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies across all laboratory strains. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies [87]. PfRh5 forms a complex with the falciparum proteins CyRPA and Ripr when interacting with erythrocyte basigin [88]; PfRh5-basigin interaction triggers remodeling of the red cell cytoskeleton to allow merozoite invasion [89].
However, it is puzzling that Ok blood group antigens are not obviously polymorphic in malaria endemic regions. Nevertheless, these findings have provoked renewed interest in further explorations of PfRh5 as a vaccine candidate antigen. Recombinant PfRh5 can induce antibodies in humans that block invasion of red blood cells by merozoites [90] and a recombinant chimeric antibody (Ab-1) against basigin inhibited the PfRH5-basigin interaction and blocked erythrocyte invasion across multiple parasite strains [91]. Intriguingly, binding of PFRh5 to basigin may be responsible for the species specificity of PfRH5 binding and provide a molecular basis for the restriction of P. falciparum to its human host among other primates [92].
RED CELLS WITH CYTOSKELETAL ABNORMALITIES — In view of the complexity of malarial invasion of the red cell [7], it is not surprising that mutations in genes encoding cytoskeletal proteins could lead to red cell resistance to P. falciparum. Protection against malaria has been associated with three genetic disorders involving the red cell cytoskeleton: Southeast Asian ovalocytosis, hereditary elliptocytosis, and hereditary spherocytosis. A discussion of the functions of the different cytoskeletal proteins can be found elsewhere. (See "Red blood cell membrane: Structure, organization, and dynamics".)
Southeast Asian ovalocytosis — Southeast Asian or Melanesian ovalocytosis (SAO), the sole highly polymorphic red cell cytoskeleton abnormality, is present in approximately 30 percent of the Melanesian population of Papua New Guinea and other aboriginal populations of Southeast Asia. It results from a specific variant (a 27 base pair deletion) in the SLC4A1 gene, which encodes band 3. Band 3 is an integral membrane protein that primarily functions as a chloride-bicarbonate exchanger; it also provides structural cohesion between the RBC membrane and the underlying spectrin-based cytoskeleton. The net effect of the SAO variant is a red cell with increased rigidity. (See "Hereditary elliptocytosis and related disorders", section on 'Differential diagnosis'.)
Epidemiologic evidence suggests that SAO confers resistance to high levels of parasitemia with P. falciparum, P. vivax, and P. malariae [93,94]. It may also protect against cerebral malaria in patients infected with P. falciparum. In one study of inhabitants of the Madang area of Papua New Guinea, for example, heterozygous SAO was present in 15 percent of all inhabitants, 9 percent of those who had uncomplicated P. falciparum malaria, and in none of those with potentially life-threatening cerebral malaria [95]. However, the prevalence of ovalocytosis did not differ between children with and without acute P. falciparum malaria, suggesting that ovalocytosis protects from dying of malaria but not from acquiring malaria [96].
These observations are consistent with in vitro studies. Melanesian ovalocytes are highly resistant to invasion by P. falciparum merozoites [97-99]. They are also resistant to invasion by P. knowlesi, a plasmodium similar to P. vivax [98]. Interestingly, a similar defect in P. knowlesi invasion can be induced in normal erythrocytes by monoclonal antibodies directed against band 3, the protein that is abnormal in SAO [100].
Why merozoites are unable to invade the ovalocytic cell is not well understood. Inhibition of invasion of two types of plasmodia suggests involvement of a later stage of invasion than receptor recognition. In vitro studies suggest that it is decreased deformability, not the ovalocytic shape per se, that is of primary importance in protecting against malaria [99] and that the degree of impaired invasion is closely related to the degree of reduced deformability [101].
There is an additional aspect to this relationship, since malaria infection also induces the generation of ovalocytes. In one series from Thailand, individuals infected with malaria had a higher percent of ovalocytes than uninfected controls (6.3 percent with P. falciparum, 8.3 percent with P. vivax, and 0.6 percent in uninfected controls) [102]. Infected ovalocytes contained significantly fewer parasites than infected discocytes, suggesting that the development of ovalocytes could represent a host response to parasite multiplication within the circulation.
Hereditary elliptocytosis — Hereditary elliptocytosis (HE) is a disorder of the red cell cytoskeleton, in which mutations in protein 4.1, alpha spectrin, beta spectrin, band 3, and glycophorin C have been described. HE red cells demonstrate resistance to invasion by both P. knowlesi and P. falciparum. Indirect evidence for protection against clinical disease comes from the observation that HE is found in high prevalence in regions in which malaria has been or is endemic. As an example, the prevalence of HE in the United States is 2.5 to 5 per 10,000 but may be greater than 1 to 10 percent in areas in which malaria is endemic [103-105]. (See "Hereditary elliptocytosis and related disorders".)
The resistance of HE cells to malarial infection may involve diminished invasion, poor intraerythrocytic growth, or diminished cytoadherence of infected erythrocytes [106]. In particular, a normal protein 4.1/glycophorin C/p55 complex appears to be important for parasite invasion and development [72]. A review of the functions of the different cytoskeletal proteins can be found elsewhere. (See "Red blood cell membrane: Structure, organization, and dynamics".)
The relevance of this protein complex for successful multiplication of the parasite is illustrated by the following observations:
●P. falciparum invasion into protein 4.1-deficient or glycophorin C-deficient red cells is greatly reduced; once inside, parasites grow normally in the latter cells but poorly in the former [72]. Since the p55 protein is deficient in both types of abnormal red cells, p55 may be important for cell invasion but not for parasite growth.
●P. falciparum parasites that generate mature-parasite-infected erythrocyte surface antigen (MESA), a protein that is thought to play a role in regulating cytoadherence, do not grow well in protein 4.1-deficient red cells. MESA binds to protein 4.1 in normal RBCs and the failure of this association in the cytoplasm of 4.1-deficient cells probably explains the accumulation of large amounts of MESA, an event that is presumably unfavorable for parasite development [71].
Less common structural variants that increase the content of spectrin dimers also exhibit impaired parasite growth [107]. This pattern is distinct from that seen in hereditary spherocytosis, in which parasite growth is diminished in proportion to the reduction in spectrin content (see 'Hereditary spherocytosis' below) [107].
There is an additional aspect to the relationship between protein 4.1 and P. falciparum. Red cell membrane proteins may become modified during intracellular growth of P. falciparum. One example is an 80 kD phosphoprotein associated with the red cell membrane of P. falciparum-infected cells. This protein appears to be a phosphorylated form of protein 4.1, since it is not seen in infected HE cells that are completely devoid of protein 4.1 [108]. The possible role of this phosphoprotein in parasite growth and survival is uncertain.
Hereditary spherocytosis — Hereditary spherocytosis (HS) is a result of heterogeneous alterations in one of five genes that encode for proteins involved in vertical associations which tie the membrane skeleton to the lipid bilayer. HS has not been reported at polymorphic frequencies in any region of the world and its role in protection against malaria is uncertain. (See "Hereditary spherocytosis".)
In an in vitro study, P. falciparum growth in HS erythrocytes showed a unique pattern [107]. Growth was normal during the first two days, followed by impaired growth, the onset of which was more rapid in cells with greater degrees of spectrin deficiency. In other experiments in ankyrin/spectrin deficient mice, spectrin appeared to be necessary for the invasion and/or growth of malarial parasites [109]. Heterozygous ankyrin-1 null mice have wild-type levels of ankyrin-1 and spectrin with normal red cell survival but are nevertheless protected from malaria. Resistance is not due to reduced invasion; the exact mechanism of protection is unclear [110].
These observations in HE and HS suggest that skeletal membrane proteins may play a role in both parasite invasion and growth, according to the defect that is present. One possible mechanism by which parasite growth is impaired, as mentioned above, is accumulation of MESA in protein 4.1-deficient cells. Other possibilities include involvement of host cytoskeletal proteins in the generation of the parasite membrane or the insertion of parasite proteins into the red cell surface [109].
Parasitization with P. falciparum also induces a loss of red cell deformability [111,112]. This effect is more prominent in more mature forms (trophozoites and schizonts) and may affect the likelihood of microvascular occlusion (and therefore the ischemic complications of severe falciparum malaria) as well as the clearance of parasitized cells by the reticuloendothelial system.
OTHER RED CELL MEMBRANE PROTEINS
The major red blood cell calcium pump — A genome-wide association study has shown that a polymorphisms that map to the major red blood cell calcium pump (ATP2B4) were associated with protection from severe malaria [55,113]. The same single nucleotide polymorphisms (SNPs) have been associated with erythroid-specific expression quantitative trait locus for ATP2B4 and with mean corpuscular hemoglobin concentration (MCHC). The genetic signal has been mapped to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer have abnormally high intracellular calcium levels and the data support ATP2B4 as a potential target for modulating red blood cell hydration in erythroid disorders and malaria infection [114].
The iron exporter ferroportin — Ferroportin is expressed on many cell types including developing and mature red blood cells. Mice with a knockout of ferroportin are more susceptible to malaria. A common polymorphism in African populations (FPN Q248H) renders the protein resistant to downregulation by the iron-regulatory hormone hepcidin and reduces intracellular iron accumulation, hemolysis and anemia, although there are conflicting reports on whether it reduces the risk of malaria or the degree of parasitemia [115,116].
The mechanically activated ion channel Piezo1 — Hereditary xerocytosis (HX) is characterized by red blood cell dehydration with mild hemolysis. Most cases of (HX) are associated with gain-of-function mutations in PIEZO1, which encodes a mechanically activated ion channel. In a mouse model with a gain-of-function mutations in PIEZO1, mice are protected from cerebral malaria with the rodent parasite Plasmodium berghei infection due to the action of Piezo1 in RBCs and in T cells [117]. A search for human alleles of PIEZO1 showed a novel human gain-of-function allele, E756del, that was present in a third of the African population. Red blood cells from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. It appears that the gain-of-function PIEZO1 allele, E756del, is associated with protection from falciparum malaria.
SUMMARY
●Mechanisms – Malarial invasion of the red blood cell is a complex process. Gene variants that affect the red blood cell membrane (eg, involving surface antigens and cytoskeletal proteins) interfere with such invasion and offer protection against malaria. The principal mechanisms of protection involve inhibition of merozoite entry into the red blood cell, impairment of intracellular parasite growth, and prevention of the erythrocyte lysis that occurs with parasite maturation. (See 'Mechanisms of protection' above.)
●Cell surface proteins – Surface antigens that offer protection include (see 'Red cell surface antigens' above):
•Duffy blood group system
•ABO(H) blood group system
•Glycophorins
•Gerbich antigen
•Complement receptor type 1
•Knops blood group
•Basigin – Ok blood group
●Cytoskeletal proteins – Abnormalities of the red cell cytoskeleton that may offer protection include the following (see 'Red cells with cytoskeletal abnormalities' above):
•Southeast Asian ovalocytosis
•Hereditary elliptocytosis
•Hereditary spherocytosis
●Membrane channels – Abnormalities of membrane channels that may also offer protection include (see 'Other red cell membrane proteins' above):
•The calcium pump encoded by ATP2B4
•The iron transporter ferroportin
•The mechanically activated ion channel Piezo1
●Hemoglobinopathies – Inherited abnormalities of hemoglobin (eg, sickle hemoglobin, thalassemia) that may offer protection are discussed separately. (See "Protection against malaria in the hemoglobinopathies".)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
