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Volume regulation is an important aspect of red blood cell (RBC) physiology that facilitates efficient transport of oxygen throughout the body. Ion channels are the key player in volume regulation allowing the movement of water and ions across the cell membrane. Dysfunction in ion channel activity can disturb the precise balance of ion transport and volume regulation, leading to the development of various disorders. Hereditary defects in RBC are well-known to provide protection against severe malaria. However, RBC’s volume disorders may also impact on malaria protection which needs thorough investigation. In recent years, PIEZO1 and ATP2B4 genes were discovered to be involved in RBC volume homeostasis. These genes through calcium-activated potassium channel (Gardos channels) regulate RBC volume and may be involved in protection against severe malaria in humans. This chapter is an attempt to cover the dynamic interplay of RBC’s volume regulation and its role in protection against severe malaria. This chapter also aims to provide insight on the complexity of genetic variants of human RBC that may affect malaria pathogenesis.
National Institute of Malaria Research, New Delhi, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
Raja Babu Kushwah
Texas A & M University, USA
Prashant K. Mallick*
National Institute of Malaria Research, New Delhi, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
*Address all correspondence to: pkmmrc01@gmail.com
1. Introduction
Red blood cell (RBC) act as an abode of malaria parasite during infection. Erythrocytic phase of malaria parasite is important for its asexual multiplication and survival [1]. Merozoites are completely developed within RBC and then released into the blood circulation. These are small, polarized, pear-shaped cells committed to invade uninfected RBC [2]. Merozoite consists of rhoptries and microneme having proteases, phospholipases, and lipids that aid in the invasion by inducing structural change on the RBC membrane [3]. A tight junction between the merozoite and RBC membrane facilitates its invasion [4]. Various parasite ligands are involved in the merozoite invasion with associated receptors on the surface of RBC. Erythrocyte binding antigen (EBA) family of proteins are the most important parasite ligands that are associated with glycophorins on RBC as receptor [5]. Another important category of parasite ligand is the reticulocyte binding proteins which interact with the complement receptor 1 (CR1) and basigin (CD147) as receptors [6]. Along with these ligands, merozoite surface proteins (MSP) are also strong candidates for invasion that mediate primary interaction with RBC [7]. Both ligands and receptors remain under natural selection, and polymorphisms on RBC membrane protein may reduce the invasion efficiency of parasite to ultimately show protection against severity of malaria [8].
After successful invasion, it alters RBC membrane, attains growth, replicates, and bursts to initiate another cycle of invasion which causes malaria pathogenesis [9]. On the other hand, various polymorphisms in RBC proteins have been reported to reduce malaria pathogenesis [10, 11]. These reported polymorphisms are either associated with ineffective invasion of merozoites or reduced growth and development within RBC, which in turn are associated with protection against the severity of malaria. Polymorphism in transporters of RBC ion channels can affect the RBC shape and volume [8, 12, 13, 14, 15]. The mechanistic explanation of how RBC volume affects the severity of malaria is an ongoing area of research. The dysregulation of membrane ion transport results into dehydration of RBC with increased fraction of dense RBC, which further reduces parasite invasion and growth [16, 17, 18, 19]. Dehydration of RBC is also a feature of different hemoglobinopathies that lowers parasitemia and severity of disease [18]. These hemoglobinopathy disorders are highly prevalent in malaria-endemic populations [20, 21]. RBC-related monogenic inherited diseases are most common due to selective pressure of malaria [17, 22]. This selective force is particularly high in malaria-endemic areas since these regions experienced high malaria transmission for a long period provide plenty of opportunity for natural selection to shape the human genome [23]. This chapter will provide an insight to RBC’s volume homeostasis that has importance in its own life cycle and how any alteration may affect the life cycle of human malaria parasites. It will focus on the variations in the channels involved in RBC volume homeostasis and their role in malaria protection. Additionally, it will explore other genetic variations present in proteins of the RBC membrane and cytoplasm and their potential role against malaria that may provide us valuable insights to improvised therapeutic strategies against malaria.
Red blood cells are prime target for the malaria parasite because of their abundance, lack of a nucleus, and availability of hemoglobin as a nutrition source [17]. RBC plays a key role in life cycle of malaria parasite as it is involved in survival and proliferation of parasite [1]. Human malaria begins with sporozoites being inoculated into the skin of a human by a female Anopheles mosquito. The sporozoites enter the liver by blood vessels and subsequently invade liver cells by passing through Kupffer cells [24]. In hepatocytes a parasite goes through schizogony where it divides into thousands of merozoites [25]. After the maturation of merozoites, infected hepatocytes rupture and released into bloodstream, where these enter into the RBC and initiate a new cycle of schizogony, where the haploid genome of parasite replicates asexually [26, 27]. During development inside RBC, parasites go through the ring, trophozoite, and schizont stage [17]. The adult schizont may comprise multiple (16–32) daughter merozoites and are released to invade fresh RBC once infected RBC (iRBC) gets ruptured [28]. This erythrocytic cycle in Plasmodium malariae takes around 72 hours, 48 hours for Plasmodium vivax, Plasmodium falciparum, and Plasmodium ovale and 24 hours for Plasmodium knowlesi [29, 30]. Apart from merozoites, ruptured RBC also produces numerous metabolic by-products, such as hemozoin, which is formed during digestion of hemoglobin. These by-product triggers immune system and causes various clinical symptoms such as fever, headache, and chills in human. Some patients may progress into severe form of malaria (cerebral malaria), acidosis, severe anemia, and death [31].
2.2 Malaria evolutionary force on RBC
Mutual evolution at both host and parasite has been observed due to long-term cellular interaction during infection [32]. In parasite the diversification is observed among proteins involved in invasion of RBC, and host showed the signature of selection on proteins interacting during parasite invasion, its growth, and host immunological genes [33]. As malaria parasite and human host co-evolved, genetic disorders are well-known to alter aspects of RBC biology and influence the malaria susceptibility or pathogenicity. In the erythrocytic phase of P. falciparum, first step of RBC and merozoite interaction is very important, and various parasite ligands are involved in its invasion with cognate receptor on the surface of RBC [5, 6, 34, 35]. Throughout the extensive evolutionary history of malaria parasites and humans, RBC has undergone various adaptive changes which include modifications in the receptors present on its surface which contribute to protection against parasite invasion in diverse geographic populations across the globe. Notable examples of such adaptations include mutations in glycophorin, complement receptor 1 (CR1), and band 3 protein. After the invasion, parasite grow and replicate inside RBC. This intracellular development is accompanied by several structural, biochemical, and functional alterations in RBC [9]. RBC proteins such as hemoglobin, intracellular enzymes, RBC ion channels, RBC surface proteins, and proteins associated with RBC shape and volume have been observed to reduce malaria pathogenesis [8, 11, 12, 13, 14, 15].
2.3 Relationship between RBC volume, calcium channels, and malaria protection
RBC volume dysregulation and malaria protection is an active area of research. The mechanisms behind the impact of RBC dehydration on malaria protection are still not fully decoded in vivo. However, in vitro studies showed that hydration of RBC plays a key role in parasite invasion and may result in the reduction of invasion efficiency or it becomes resistant to invasion of parasite [18]. Calcium channels play a key role in regulation of ion concentration and cell volume. These are indirectly involved in volume regulation by controlling the activity of other ion channels that directly affect RBC volume [36, 37]. RBC calcium homeostasis is maintained primarily by the calcium channels PMCA1 (plasma membrane calcium ATPase 1), PMCA4 (plasma membrane calcium ATPase 4), PIEZO1 (piezo type mechanosensitive ion channel component 1), eNMDARs (erythroid N-methyl D-aspartate receptor), and Gardos channels. Gardos channel is important in volume regulation of RBC and activated by increased intracellular calcium concentration. This channel plays a role during RVD by decreasing the ionic concentration inside RBC which causes efflux of potassium (K+) ion followed by loss of water [38]. Out of all these channels, ATPase plasma membrane calcium transporting 4 (ATP2B4) and PIEZO1 emerge as strong candidates in malaria protection at various parts of the world. Both genes are involved in calcium homeostasis and dehydration of RBC. In human RBC, ATP2B4 gene encodes plasma membrane calcium ATPase (PMCA4). PMCA4 is an active calcium pump in RBC membrane and is involved in regulation of cellular calcium level [36]. Recently PIEZO1 channel is also identified in RBC membrane as a mechanosensitive, non-selective cation channel, and it is also permeable for calcium [39]. It also involved in RBC volume regulation by robust calcium influx [40, 41]. Clinical severity in sickle cell disease was observed due to RBC dehydration [42], and in contrast same phenomenon is involved in protection from malaria parasite [18]. This finding is supported in different malaria endemic population by GWAS and population-based studies, where genetic variation present in calcium channels of RBC has been linked with protection to severe P. falciparum malaria [11, 43, 44, 45, 46].
Natural function of red blood cell and its volume are maintained by the complex interaction between semi-permeable cell membrane and osmotic gradient. Understanding interaction permeability and osmotic gradient is essential to study the role of RBC in oxygen transport and in different diseases related to RBC physiology [47]. RBC membrane is selectively permeable, allows the free movement of water molecules (100 μm/s), and impermeable to most of the solutes inside the cell. Aquaporin water channels are essential for water exchange and osmotic water exchange, which supports in osmoregulation depending on the external environment [48]. Electrical neutrality persists on both sides of the plasma membrane at a steady state of cell, and diffusible ion concentrations remain equivalent on both sides of semi-permeable membrane as per Gibbs-Donnan equilibrium [49]. However, overall concentration of intracellular molecules is significantly higher than the concentration of extracellular molecules due to the existence of non-diffusible intracellular protein. Because of this concentration gradient, obligatory water movement occurs and creates osmotic gradient, so at steady state, this osmosis can cause cell swelling and eventually cell death [50]. In active transport of ions, Na+/K+ ATPase is the main player, where three sodium (Na+) ions pump out of the cell in exchange for two potassium (K+) ions to prevent cellular osmoexplosion [51].
3.1.1 Aquaporins
Aquaporins (AQP) are one of the major contributors in osmoregulation of a cell. These are integral membrane proteins which facilitate bidirectional water flow driven by osmotic pressure [52]. Along with water it also transports gases, glycerol, ammonia, and ions in a selective manner. In mammals, 13 aquaporins from AQP0 to AQP12 have been identified which are different in their water permeability and size [53, 54]. All AQPs possess a conserved structure consisting of six transmembrane alpha-helices which form a barrel-like configuration and two short alpha-helix domains on periplasmic and cytoplasmic side of the barrel. These domains contain asparagine-proline-alanine (NPA) motif which is AQP family’s signature, also viewed as the “hourglass model” [55]. RBC has AQP1, formerly known as CHIP28 (channel-forming integral protein 28) is the most studied in water channels [56], and it is also expressed on central nervous system (CNS), kidneys, inner ears, lungs, eyes, and skeletal muscles [57]. One of the rare blood group systems, i.e., Colton blood group (CO) has been associated with AQP1 [58].
3.2 Active mechanisms
RBC volume regulation involves both passive and active mechanism, together these mechanisms ensure that the volume of RBC remains within the range for overall physiological balance. The primary means to regulate RBC volume is by means of control on the cell’s solute concentration across plasma membrane results in modulation of intracellular water content [59]. Different ion channels present in RBC membrane are responsible for achieving electrochemical concentration gradient and hence regulate the cell volume. At steady-state, osmoexplosion is prevented, and RBC volume is maintained by Na+/K+ ATPase. It actively transports K+ ions into the cell and Na+ ions out of the cell, against their electrochemical gradients [51]. The K+ ions further recycled through K+ channels, and ATP is rapidly resynthesized from ADP and inorganic phosphate. This mechanism is called double Donnan mechanism or pump-leak balance, as shown in Figure 1 [48].
Figure 1.
Schematic illustration of the mechanisms for regulatory volume increase (RVI) and regulatory volume decrease (RVD) under different physiological conditions. In steady state under isotonic conditions, cell volume regulation occurred by the “double-Donnan” or “pump-leak balance” mechanism via the Na+, K+ pump in RBC. In hypertonic and hypotonic conditions, RVI and RVD occurred by different ion channels (see in text for details).
RBC can readjust their volume rapidly in response to various environment changes like in transient anisotonic conditions. This readjustment is mediated by number of channels and transporters which results in the net flow of osmolytes and osmotically obligated water, as described in Table 1. However, cell experience hypertonic and hypotonic stress after that [48]. There are two ways of regulating cell volume in anisotonic conditions; regulatory volume increase (RVI) and regulatory volume decrease (RVD) in hypertonic and hypotonic conditions, respectively [60].
Ion channels involved in RBC volume regulation and its associated disorders.
In hypertonic environment when osmotic cell shrinkage occurs, RVI is achieved by net influx of sodium chloride (NaCl) and water. There are three different cotransporter-mediated mechanisms responsible for RVI; (1) operation of Cl− −HCO3− antiporters (anion exchanger AE or band 3) and Na+-H+ antiporter (NHE) parallelly, (2) operation of Na+-Cl− symporter (NCC), (3) operation of Na+-K+-2Cl− symporter (NKCC) in different cell type [61, 62, 63]. In hypotonic condition when osmotic cell swelling occurs, RVD is achieved by net potassium chloride (KCl) efflux. RBC transporters involved in this are K+ and Cl− symporter (KCC) or Cl− channels like K+-Cl− symporter, Cl−-HCO3− (AE or band 3 protein) antiporters [64]. RVD and RVI are essential in maintaining osmotic balance and ensure that RBC neither swells or shrinks excessively to preserve its structural integrity. It also allows RBC to adapt as per external environment during diverse physiological conditions.
3.3 Calcium channels in RBC
Calcium ions (Ca2+) are indirectly involved in either osmotic balance or hydration activity of RBC; however, it involves in the regulation of different ion channels which play prominent role during water homeostasis of RBC [37]. Apart from this, calcium homeostasis of a cell is important for various reasons as calcium acts as a universal signaling molecule and also involves in regulation of cell cycle, motility, and structural integrity [65]. RBC differentiation is also relied on Ca2+-dependent signaling [65]. After differentiation, mature RBC lacks intracellular calcium storage organelles such as endoplasmic reticulum, and the whole calcium homeostasis depends on the calcium channels of plasma membrane. A balance between active calcium extrusion and passive calcium influx supports in the maintenance of low cytoplasmic calcium concentration Ca2+ (30–60 nM) as compared to high blood calcium concentration (1.8 mM) [36]. Low intracellular calcium concentration is important for RBC physiology as it can become dehydrated, if not able to maintain the low intracellular calcium concentration, as in the case of sickle cell disease and RBC aging. During increased intracellular calcium, a calcium-activated potassium channel, i.e., Gardos channels become activated which causes potassium efflux, water loss, and consequently, RBC volume loss called as Gardos effect [66, 67].
4. Genetic evolutions in RBC towards tolerance to malaria
Malaria has been a strong evolutionary force that can be evidenced at different populations which have developed independent genetic variations for protection against severe malaria [68]. Most of the genetic variation developed is related to the RBC structure and function [9]. Major of the protective variations lie among surface proteins of RBC involved in parasite invasion and proteins involved in RBC’s physiology affecting parasite growth and replication. Below is the detailed description of variation in proteins of RBC cell membrane and changes induced by malaria parasite selection pressure affecting its physiology.
4.1 Variations on RBC cell membrane affecting parasite invasion
4.1.1 Glycophorins and MNS blood group
Glycophorins are the most abundant sialo-glycoproteins on human erythrocyte membranes which act as receptors for various pathogens, including Plasmodium spp. Genetic variations in the glycophorin region (GYPA, GYPB, and GYPE genes) on chromosome-4 are of interest, particularly the Dantu hybrid glycophorin variant associated with a 40% reduction in severe malaria incidence in East African communities [69]. Glycophorins play a key role in malaria parasite invasion of erythrocytes, with GPA and GPB served as receptors for P. falciparum ligands like EBA-175 [70]. The GYPA and GYPB genes also contribute to the MNS blood group system [71], and their fusion produced the rare blood group Dantu [72]. Absence of glycophorins on RBC surfaces is linked with protection against malaria. An En(a-) mutation lacking Glycophorin A is associated with P. falciparum malaria protection [73, 74, 75] and a haplotype, including GYPA, GYPB, and Dantu, provided 33% protection from severe falciparum malaria [8, 76]. Dantu’s effect on P. falciparum merozoite invasion of RBC is linked to changes in the RBC surface protein repertoire. Video microscopy revealed a significant correlation between RBC tension and merozoite invasion, with Dantu cells exhibited higher average surface tension, providing an explanation for the protection from malaria [77].
4.1.2 SLC4A (hereditary elliptocytosis)
Band 3, encoded by the SLC4A gene, is an important glycoprotein in the RBC membrane. It facilitates chloride and bicarbonate exchange and also vital for carbon dioxide respiration [78]. Band 3 also plays a key role in P. falciparum invasion as a host receptor for merozoite surface protein 1 (MSP1) [7]. Heterozygous deletion of codons in band 3 causes the ovalocytotic phenotype in a RBC membrane disorder called as Southeast Asian ovalocytosis (SAO) [79]. Individuals with heterozygous SAO show reduced RBC anion transport and altered RBC membrane protein structures [80]. Interestingly, SAO mutations confer resistance to both P. vivax and P. falciparum malaria [81, 82]. Homozygotes for the ovalocytosis allele may face mortality risks, but heterozygotes have an advantage against malaria [83]. The protective mechanism involves an aberrant band 3 protein binding tightly to ankyrin in cytoskeleton, increasing RBC stiffness and resisting invasion of malaria parasite [84].
4.1.3 DARC
DARC (Duffy antigen receptor for chemokines), is a glycosylated membrane protein with seven transmembrane domains encoded by FY gene. It acts as a non-specific receptor for various chemokines and serves as the entry receptor for P. vivax [85] and P. knowlesi [86, 87]. The FY*ES allele is associated with the absence of the Duffy antigen, and prevalent in Sub-Saharan Africa, indicates strong positive natural selection due to its role in malaria resistance [88, 89]. Polymorphism in DARC is one of the key examples of malaria exerting selective pressure on the human genome [86, 88, 90, 91].
4.1.4 ADGRE1 (EMR1)
EGF-Like Module Receptor 1 (EMR1) encodes a transmembrane glycoprotein resembling G protein-coupled receptors, having cell-adhesion and cell-cell interaction properties [92]. EMR1 is associated with malaria susceptibility as polymorphisms (e.g., rs373533) showed associations with malaria-associated seizures and hyperpyrexia among African populations [93, 94]. A genome-wide study on P. chabaudi observed significant changes in DNA methylation, affecting the expression of seven genes, including EMR1. These alterations were associated with differentially methylated promoters, suggesting a potential epigenetic influence on the host’s response to malaria. Its exact role in malaria protection remains unclear, however, highlighted the complex relationship between epigenetic modifications and malaria protection [95].
4.1.5 ABCB6
ATP binding cassette subfamily B member 6 (ABCB6), a member of the ATP-binding cassette transporter family, acts as a porphyrin transporter in nucleated cells for heme biosynthesis. ABCB6 is responsible for the Lan blood group antigen on RBC. Individuals lacking Lan (Lan null) are asymptomatic, and ABCB6’s role in adult human erythrocytes is unclear [96, 97]. Erythrocytes lacking the Lan protein demonstrate protection to invasion by P. falciparum parasites. Interestingly porphyrin accumulation or porphyrin-induced toxicity is not the reason behind this protection, which implies that in Lan null RBC, protective role operates independently of LAN’s porphyrin transport function.
4.2 Variations in RBC physiology affecting parasite growth
RBC physiological variation includes gene responsible for altered growth of parasite inside RBC; it includes oxidative stressed genes, hemoglobinopathies, enzymopathies, and RBC volume alteration [68]. The role of oxidative stress in the early clearance of iRBC is closely linked to the activity of key genes, such as G6PD and NOS2. G6PD plays a key role in maintaining cellular redox balance, while NOS2 contributes to the generation of reactive nitrogen species, collectively influencing the dynamics of iRBC clearance during the course of infection [98].
4.2.1 G6PD
Glucose-6-phosphate dehydrogenase (G6PD) gene on the X-chromosome encodes key enzyme protecting erythrocytes from oxidative stress caused by reactive oxygen species. G6PD deficiency, an X-linked recessive condition affecting around 400 million people globally, is associated with a reduced risk of malaria [99]. G6PD-deficient RBC showed a reduction in growth of P. falciparum parasite in in vitro study [100]. Studies in African children demonstrated a 46–58% lower risk of severe malaria in G6PD-deficient individuals supporting a selective advantage in malaria-prone regions [101]. The most common G6PD variant named Mahidol is associated with reduced P. vivax density in Southeast Asia and showed strong positive selection over the past 1500 years driven by malaria [102].
4.2.2 NOS2
Inducible nitric oxide synthase (iNOS) encoded by the nitric oxide synthase 2 (NOS2) gene generates nitric oxide (NO), a free radical with antiparasitic effects. However, NO’s immunosuppressive impact and its potential role in malaria protection is unclear. In a Gabonese study, the A954C allele of NOS2 was associated with elevated NO synthase activity, providing protection from severe malaria and reinfection [103]. Another study conducted among Tanzanian and Kenyan children suggested that polymorphisms in the NOS2 gene promoter region enhance NO production, which has a potential antimalarial effect [104].
4.2.3 Hemoglobinopathies
Hemoglobinopathies are the genetic abnormalities in hemoglobin’s structure and function. It encompasses variations like structural hemoglobin anomalies and thalassemia, affecting the production of hemoglobin. The Hemoglobin Subunit Alpha (HBA) genes (HBA1 and HBA2) and Hemoglobin Subunit Beta (HBB) gene, encoding α- and β-globins, respectively, are located on chromosomes 11 and 16 [105]. One variable HBB gene is HbAS allele causes sickle cell trait, a polymorphism observed at 10% frequency in many malaria-endemic regions [106]. HbAS leads to sickle-shaped erythrocytes under low oxygen conditions, offering protection against severe malaria. This protection is linked to mechanisms like enhanced phagocytosis of infected HbAS erythrocytes and reduced parasite growth and invasion [107, 108, 109, 110] and shows 10-fold lower risk of severe malaria [111, 112].
Hemoglobin C carriers also demonstrate protection against malaria [113]. Hemoglobin C alters the surface characteristics of P. falciparum-infected erythrocytes, reduces its adhesion to endothelial cells, and minimizes sequestration in the microvasculature. Various association studies, including one in the Luo tribe of Kenya, provide evidence of the HBB gene’s role in malaria resistance. Overall, these genetic variations showcase the intricate interplay between hemoglobinopathies and malaria susceptibility, highlighting the complex evolutionary adaptations in diverse populations [114].
4.3 Variations among RBC calcium channels affecting parasite growth
Recent studies have expanded our understanding about the evolutionary adaptations in humans and suggested that calcium channels also play a key role in malaria protection. Understanding how variations in calcium channels affect the RBC’s response to parasite infection may add a new layer to the whole phenomenon. Here are some of the recently discovered genetic variation related to calcium channels.
4.3.1 PIEZO1 (FAM38A)
PIEZO1 is a mechanosensitive, non-selective cation channel. It aids in sensing mechanical stimuli in various multicellular organisms [115]. In vertebrates, PIEZO1 and PIEZO2 are present with homologs in invertebrates regulating blood pressure and RBC volume [116, 117]. Gain-of-function mutations in PIEZO1 gene have been associated with dehydrated hereditary stomatocytosis (DHS) [118, 119]. A new gain-of-function mutation observed in PIEZO1 gene, prevalent in one-third of people of African decedent has been shown inhibited Plasmodium infection [45]. This mutation (E756Ddel) characterized by TCC deletion specifically removes one glutamic acid from a stretch of seven in wild type. This deletion leads to increased calcium influx in RBC and activates the Gardos channel to cause RBC dehydration. Mouse model for hereditary xerocytosis (HX) has demonstrated that Plasmodium infection does not generate experimental cerebral malaria in these mice due to PIEZO1 activation among RBC and T cells [45]. The heterozygosity for E756del did not provide additive protection in sickle cell trait (HbAS) patients, whereas homozygosity was linked to an increased risk of severe illness, implying an epistatic interaction between HbAS and PIEZO1 E756del. Surface protein analysis in heterozygotes revealed low expression of the P. falciparum virulence protein named Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) [120]. Despite this, a study conducted in Ghana observed no significant association between them [121]. The actual mechanism of protection is not known but compound Yoda-1, a PIEZO1 activator, prevents P. falciparum invasion into RBC without affecting intraerythrocytic growth, and suggests a mechanism unrelated to RBC dehydration or ion imbalance [122].
4.3.2 ATP2B4
The ATP2B4 gene encodes a P-type primary ion transport ATPase that removes bivalent Ca2+ ion from the eukaryotic cell against high concentration gradient and play important role in calcium homeostasis. PMCA4 serves as a key exporter of Ca2+ ion in case of human RBC and expression analysis showed a lower PMCA4 expression caused an impaired calcium efflux from the RBC. About 1.58 to 1.67-fold higher overall Ca2+ ion levels were observed in RBC with low PMCA4 when compared to RBC with average level of PMCA4. This study observed mutations in the promoter region that was highly correlated with this lower PMCA4 protein levels [123]. Till date, Gardos-mediated dehydration of RBC due to the mutant ATP2B4 gene is only possible mechanism explained for the malaria protection, and mechanistic link is yet to be established [44]. Population-based and in vitro studies showed variation in ATP2B4 gene is associated with increased MCHC [11] that protect from mild and severe malaria [10, 124]. In addition, low PMCA expression [44, 123] reduced parasite density [125] and slow growth of falciparum [126], which may attribute to protection against severity in malaria [18]. Recent study showed inhibition of PMCA4 by aurintricarboxylic acid (ATA), and Resveratrol can cease the growth of P. falciparum inside RBC [127].
4.3.3 KCNN4
KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) gene encodes for Gardos channels which are calcium-activated potassium channels and regulated by intracellular calcium. Its activation is followed by membrane hyperpolarization and loss of KCl and water from the RBC. Its role in malaria protection in sickle cell disease is uncertain, and the Gardos channels inhibitor Senicapoc effectively reduced RBC dehydration. The compound Senicapoc demonstrated inhibition of Plasmodium development inside RBC in in vitro studies. While, administration of Senicapoc led to a reduction in Plasmodium yoelii parasitemia in mice, indicating its potential as an antimalarial agent through its influence on RBC hydration dynamics [46].
Interestingly, various ion channels within red blood cells, including those discussed here, have been associated with disorders related to cell volume regulation, such as stomatocytosis, dehydrated hereditary xerocytosis, and ovalocytosis (as illustrated in Table 1). These volume-related disorders have been intriguingly linked with protection against malaria in diverse human populations residing in malaria-endemic regions [17]. These volume-related variations underscore the interactions among malaria protection and RBC volume regulation. It presents different prospects for the development of novel therapeutic approaches and for the improvement of our knowledge of the complex interaction between human hosts and malaria parasites.
4.4 Disorders in RBC volume regulation in response to malaria pressure
Erythrocyte dehydration is classified into primary and secondary categories. Primary disorders, such as hereditary xerocytosis syndromes, are intrinsic volume regulation disorders that directly lead to erythrocyte dehydration. On the other hand, secondary dehydration is linked to various diseases which influence the RBC hydration. In both classes, understanding the role of ion channels is important not just for understanding problems associated with RBC dehydration but also for investigating possible links to disease like malaria, where changes in RBC hydration state affect its defenses against the malaria parasite. Disorders like hemoglobinopathies, thalassemia, sickle cell disease, hereditary spherocytosis, and Southeast Asian ovalocytosis showed a significant role of erythrocyte dehydration in associated pathophysiology [128]. One more RBC condition known as hereditary xerocytosis (HX) is also marked by increased cellular dehydration. Dehydration of red blood cells has been linked with mutations in genes including PIEZO1, KCNN4, and ATP2B4. It is interesting to note that these genes have been linked to both providing protection against malaria and the pathophysiology of HX. Prior research has linked PIEZO1 and KNCC4 to RBC dehydration but no direct association has been found between ATP2B4 and any dehydration disorder. However, increased calcium levels in RBC, which are facilitated by these genes, activate the Gardos channels, resulting in cellular dehydration, which is the hallmark of HX. The resultant alterations in RBC hydration contribute to a protective effect against malaria [18], highlighting the intricate interplay between genetic factors, ion homeostasis, and the RBC’s response to malaria.
The role of membrane proteins, enzymopathies, and RBC hemoglobinopathies in malaria protection has been thoroughly investigated. However, limited knowledge of altered volume in RBC due to defects in calcium channels need more investigations to add new perspective toward the context of malaria susceptibility. The Gardos effect, activated by calcium influx, influences RBC dehydration and also linked to the severity in malaria outcomes. In conclusion, studies of RBC volume-regulating ion channels—specifically, calcium channels, and their role on malaria protection provide a unique perspective in the context of malaria susceptibility.
Pharmaceutical research on inhibitors to Gardos channels and PMCA and activators of PIEZO1 highlight the potential of targeted treatment strategies in case of malaria. The compound Senicapoc, a Gardos channels inhibitor, inhibits growth of P. falciparum as well as treats RBC’s dehydration in sickle cell disease. The compound Yoda-1 showed collective inhibition of PMCA and activation of PIEZO1 that indicates complex relationship between calcium homeostasis and malaria as it prevents invasion of Plasmodium. Despite the previous research, a complete understanding of links between alterations of RBC volume, calcium channels, and malaria protection remains a growing narrative. This chapter is an attempt to navigate the unexplored areas of research in calcium homeostasis of RBC, and it is anticipated to serve as a foundation for avenues toward new approaches in the fight against malaria (Figure 2).
Figure 2.
Calcium ion channels of red blood cell (RBC). Mutation in these channels leads to increased intracellular Ca2+ ion concentration (depicted by yellow arrow). This increased intracellular calcium concentration triggers the hyperpolarization, loosening of cytoskeleton, and Gardos effect, leading to excessive potassium efflux through Gardos channels and subsequent loss of water from the RBC. Consequently, the RBC undergoes dehydration.
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Written By
Priya Agrohi, Raja Babu Kushwah and Prashant K. Mallick
Submitted: 19 February 2024Reviewed: 17 April 2024Published: 29 August 2024
Open access peer-reviewed chapter - ONLINE FIRST
