**3. Erythrocyte and merozoite membrane proteins: participate in**  *P. falciparum* **invasion process**

The remodeling of the structures of the human erythrocytes for parasite of the malaria is generated between the process of invasion of merozoites. During the process, the parasite induces a transitory alteration of the structure of the membrane of the host cell, binging sites of the surface cellular [14]. More than 50 *P. falciparum* proteins have been identified which induce the process of invasion; however, some functional classes of elements such as merozoite surface protein (MSPs) have been described, which have demonstrated a structural complex around the envelope of the merozoites, related to PfEBAs (*P. falciparum* erythrocyte binding antigens) and PfRHs (*P. falciparum* reticulocytes binding protein), which are able of save organelles as micronemes and rhoptries [15–17].

In general, the erythrocyte membrane changes are set in motion with the merozoite invasion process. It has been described that the initial interaction between the merozoite and erythrocyte is probably a random collision, depending on the function of actin-myosin binding and specific molecular interactions between merozoite ligands and erythrocyte membrane receptors, which mediate cellular recognition and invasion of red blood cells [18]. This invasive process is carried out in four steps. The first step, called the initial contact with merozoite, takes place mainly by the interaction of proteins that are uniformly distributed on the surface of the merozoite, called glycosyl-phosphatidyl-inositol protein (GPI), with erythrocyte surface ligands, such as merozoite surface protein 1 (MSP1), whose receptor is band 3 protein in the erythrocyte membrane [19, 20]. The second step is called reorientation, which is produced for vertical arrangement of apical secretory organelles, such as rhoptries and micronemes. This step is mediated by a protein called apical membrane Antigen-1 (AMA1), which seems to establish the apical interaction of the adhesins with the erythrocyte; it is the border point between the weak union that occurs in the initial contact with MSP1 and irreversible bonds that occur between microneme proteins and erythrocyte membrane proteins [21, 22]. The third step is the tight-binding formation between various adhesins produced at the apical end of the parasite and its membrane receptors in the red blood cell, where the Duffy binding-like proteins (DBL) and reticulocyte binding proteins (RBP) bind. For example, surface DBL proteins of merozoite EBA 175 and EBA 140 (erythrocyte binding antigen 175 and 140) bind to erythrocyte membrane sialoglycoproteins, such as glycophorin A and C [23, 24]. On the other hand, while PfRh proteins bind to complement receptor 1 (CR1), signalization established by sensitive chymotrypsin receptor pathway and resistant to neuraminidase takes place [23, 25]. Once the parasite and erythrocyte tight junction is established, intake is mediated by the actin-myosin motor activation on the merozoite surface. This coincides with lipid and protein secretion, such as organelle-released proteases called rhoptries, micronemes, and mononemes. These proteases are associated to perform integral membrane proteins cleavage, such as band 3 and rupture of the membrane cytoskeletal proteins [26, 27].

During the invasion, proteins from the rhoptries and dense granules are secreted into the parasitophorous vacuole, and once it has developed to the ring phase, these proteins are exported to the cytoplasm of the infected erythrocyte to trigger the succession of effects of remodeling at the level of the host cell. It has been established that *P. falciparum* is capable of associating with Knobs, which are related

**53**

**Figure 4.**

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria*

to Knobs-proteins rich in histidines (KHARP). This type of formations allows the presentation of cytoadherence proteins exported by the parasite, which are coupled to the membrane, as is the case in particular of *P. falciparum* of erythrocyte membrane

**4.** *P. falciparum* **export proteins modify the erythrocyte membrane.**

by a replicative phase. The parasite modifies the host cell during the intra-erythrocytic period, conditioning it as its new habitat. It induces the formation of new permeability pathways, allowing it to provide itself with essential nutrients, dispose of waste products, modify the electrolytic composition, and decrease the colloid osmotic pressure of the erythrocyte, in order to survive in this new environment [29]. The infected erythrocyte enlarges in size, developing the formation of parasitophorous vacuole (PV), parasitophorous vacuole membrane (PVM), new membranous structures, such as the Maurer's clefts (MC), tubulovesicular networks (TVN), and erythrocyte surface protrusion appearance called Knobs. Moreover, new type of channels in the PVM and alterations of the erythrocytic membrane channels are formed, in which virulence proteins are trafficked [7, 29, 30]. In addition to MC and TVM, other structures have been described, which are involved in export protein trafficking, such as electron-dense vesicles (EDV), vesicle-like structures (VLS), J points or J-Dots, named for J-domain proteins [31–34].

*Glucose-6-phosphate dehydrogenase (G6PD) pathway. G6PD, glucose-6-phosphate dehydrogenase, GPX, glutathione peroxidase; GR, glutathione reductase, 6PG, 6-phosphogluconate dehydrogenase; GSH, glutathione* 

*reduced; GSSG: glutathione oxidized. Adapted from Cappellini and Fiorelli [92].*

Once inside the erythrocyte, *P. falciparum* is subjected to a trophic phase, followed

Subsequently, the parasite invaginates the erythrocyte through a protein-free zone and initiates the formation of parasitophorous vacuole, which continues with a motility mechanism to enter the host cell. Rhoptries and dense granules secrete proteins during the invasion early ring phase, which are trafficked to different structures, such as parasitophorous vacuoles, cytosol, and erythrocyte membrane,

*DOI: http://dx.doi.org/10.5772/intechopen.83700*

triggering a series of events that modify the host cell [28].

protein 1 (PfEMP1) [27].

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria DOI: http://dx.doi.org/10.5772/intechopen.83700*

to Knobs-proteins rich in histidines (KHARP). This type of formations allows the presentation of cytoadherence proteins exported by the parasite, which are coupled to the membrane, as is the case in particular of *P. falciparum* of erythrocyte membrane protein 1 (PfEMP1) [27].

Subsequently, the parasite invaginates the erythrocyte through a protein-free zone and initiates the formation of parasitophorous vacuole, which continues with a motility mechanism to enter the host cell. Rhoptries and dense granules secrete proteins during the invasion early ring phase, which are trafficked to different structures, such as parasitophorous vacuoles, cytosol, and erythrocyte membrane, triggering a series of events that modify the host cell [28].

#### **4.** *P. falciparum* **export proteins modify the erythrocyte membrane.**

Once inside the erythrocyte, *P. falciparum* is subjected to a trophic phase, followed by a replicative phase. The parasite modifies the host cell during the intra-erythrocytic period, conditioning it as its new habitat. It induces the formation of new permeability pathways, allowing it to provide itself with essential nutrients, dispose of waste products, modify the electrolytic composition, and decrease the colloid osmotic pressure of the erythrocyte, in order to survive in this new environment [29].

The infected erythrocyte enlarges in size, developing the formation of parasitophorous vacuole (PV), parasitophorous vacuole membrane (PVM), new membranous structures, such as the Maurer's clefts (MC), tubulovesicular networks (TVN), and erythrocyte surface protrusion appearance called Knobs. Moreover, new type of channels in the PVM and alterations of the erythrocytic membrane channels are formed, in which virulence proteins are trafficked [7, 29, 30]. In addition to MC and TVM, other structures have been described, which are involved in export protein trafficking, such as electron-dense vesicles (EDV), vesicle-like structures (VLS), J points or J-Dots, named for J-domain proteins [31–34].

#### **Figure 4.**

*Glucose-6-phosphate dehydrogenase (G6PD) pathway. G6PD, glucose-6-phosphate dehydrogenase, GPX, glutathione peroxidase; GR, glutathione reductase, 6PG, 6-phosphogluconate dehydrogenase; GSH, glutathione reduced; GSSG: glutathione oxidized. Adapted from Cappellini and Fiorelli [92].*

*Malaria*

band 4.2 proteins [12, 13].

*P. falciparum* **invasion process**

elles as micronemes and rhoptries [15–17].

as band 3 and glycophorin A and C. Finally, anchoring proteins have the function of connecting the cytoskeleton proteins with integral proteins, such as ankyrins and

The remodeling of the structures of the human erythrocytes for parasite of the malaria is generated between the process of invasion of merozoites. During the process, the parasite induces a transitory alteration of the structure of the membrane of the host cell, binging sites of the surface cellular [14]. More than 50 *P. falciparum* proteins have been identified which induce the process of invasion; however, some functional classes of elements such as merozoite surface protein (MSPs) have been described, which have demonstrated a structural complex around the envelope of the merozoites, related to PfEBAs (*P. falciparum* erythrocyte binding antigens) and PfRHs (*P. falciparum* reticulocytes binding protein), which are able of save organ-

In general, the erythrocyte membrane changes are set in motion with the merozoite invasion process. It has been described that the initial interaction between the merozoite and erythrocyte is probably a random collision, depending on the function of actin-myosin binding and specific molecular interactions between merozoite ligands and erythrocyte membrane receptors, which mediate cellular recognition and invasion of red blood cells [18]. This invasive process is carried out in four steps. The first step, called the initial contact with merozoite, takes place mainly by the interaction of proteins that are uniformly distributed on the surface of the merozoite, called glycosyl-phosphatidyl-inositol protein (GPI), with erythrocyte surface ligands, such as merozoite surface protein 1 (MSP1), whose receptor is band 3 protein in the erythrocyte membrane [19, 20]. The second step is called reorientation, which is produced for vertical arrangement of apical secretory organelles, such as rhoptries and micronemes. This step is mediated by a protein called apical membrane Antigen-1 (AMA1), which seems to establish the apical interaction of the adhesins with the erythrocyte; it is the border point between the weak union that occurs in the initial contact with MSP1 and irreversible bonds that occur between microneme proteins and erythrocyte membrane proteins [21, 22]. The third step is the tight-binding formation between various adhesins produced at the apical end of the parasite and its membrane receptors in the red blood cell, where the Duffy binding-like proteins (DBL) and reticulocyte binding proteins (RBP) bind. For example, surface DBL proteins of merozoite EBA 175 and EBA 140 (erythrocyte binding antigen 175 and 140) bind to erythrocyte membrane sialoglycoproteins, such as glycophorin A and C [23, 24]. On the other hand, while PfRh proteins bind to complement receptor 1 (CR1), signalization established by sensitive chymotrypsin receptor pathway and resistant to neuraminidase takes place [23, 25]. Once the parasite and erythrocyte tight junction is established, intake is mediated by the actin-myosin motor activation on the merozoite surface. This coincides with lipid and protein secretion, such as organelle-released proteases called rhoptries, micronemes, and mononemes. These proteases are associated to perform integral membrane proteins cleavage, such as

band 3 and rupture of the membrane cytoskeletal proteins [26, 27].

During the invasion, proteins from the rhoptries and dense granules are secreted

into the parasitophorous vacuole, and once it has developed to the ring phase, these proteins are exported to the cytoplasm of the infected erythrocyte to trigger the succession of effects of remodeling at the level of the host cell. It has been established that *P. falciparum* is capable of associating with Knobs, which are related

**3. Erythrocyte and merozoite membrane proteins: participate in** 

**52**


**55**

**erythrocyte**

pyruvate kinase [56, 57].

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria*

**weight (kDa)**

28.9 Generating the

Transmembrane 83 ND [54]

Maurer's clefts or in protecting proteins within these structures

**Putative function References**

[53]

**Protein Location Molecular** 

Erythrocyte membrane

*Proteins from the export of P. falciparum that modify post-invasion erythrocyte [6, 9].*

Another host cell modification refers to *P. falciparum* infected erythrocyte cytoadherence to endothelial cells, resulting in a sequestration of mature parasites in capillaries and microvasculature [35]. The sequestration probably leads to microcirculation alterations and metabolic dysfunctions, which could be responsible for severe malaria manifestations [36]. The cytoadherence to endothelial cells confers at least two advantages for the parasite: (1) a more suitable microaerophilic environment for parasite metabolism and (2) evasion to splenic circulation, where infected erythrocytes would be destroyed [36–39]. *P. falciparum* exports its proteins to the erythrocyte cytoplasm, where it binds to cytoskeletal components and alters the natural interactions of the membrane structural proteins, in order to achieve these major changes in the erythrocyte structure. Export proteins are encoded by 8% of *P. falciparum* parasite genome. It corresponds to host cell exported proteins, both in asexual and gametophytic phases. **Table 1** lists the main *P. falciparum* export proteins, which participate in the remodeling process and present PEXEL motifs. However, non-PEXEL proteins such as PfEMP1, SURFIN, and Pf332 are also shown in **Table 1**, due to their importance in

the infected erythrocyte remodeling process, but only PfEMP1.

**5. Mechanism of resistance to malaria and effect of** *P. falciparum* **in** 

Currently, a global distribution of erythrocyte polymorphisms has been described, such as hemoglobinopathies (thalassemia's, HbS, HbC, and HbE) and enzymatic alterations such as glucose-6-phosphate dehydrogenase deficiency (G6PD), which have their origin in response to the selective pressure exerted by

Parasites of the genus *Plasmodium* have co-evolved over 200 million years with the human species [55]. In this way, the increase of migrations in multiple regions and the establishment of settlements in certain areas have influenced the increase in endemicity produced by the successive exposure of the etiological agent of the disease; this high effect of selective pressure of the parasite has co-influenced the development of genetic variations linked to endemic populations, from which they have emerged over time polymorphic variants in erythrocytes in order to respond to the most severe symptoms of the disease, hindering the survival of the parasite or preventing the development of its entire life cycle. Many of these variations may be due to changes in structural proteins of the erythrocyte, alterations in hemoglobin (thalassemia's and sickle cell anemia), or an incidence in the quantitative and functional level of enzyme activity involved in oxidative processes such as G6PD or

*DOI: http://dx.doi.org/10.5772/intechopen.83700*

associated histidinerich protein 1

> exported protein 1

MAHRP1 Membrane-

REX-1 Ring-

*ND, nondeterminate.*

**Table 1.**

**Name of identification** Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria DOI: http://dx.doi.org/10.5772/intechopen.83700*


#### **Table 1.**

*Malaria*

**Name of identification**

KAHRP Knob-

MESA/PfEMP2 Mature

RESA/PF155 Ring-

GBP130 Glycophorin

PfEMP3 *P. falciparum*

PfEMP1 *P. falciparum*

RIFIN Repetitive

STEVOR Subtelomeric

SURFIN 4.2 Surface-

Antigen 332 (Pf332)

associated histidinerich protein

parasiteinfected erythrocyte surface antigen

infected erythrocyte surface antigen

*P. falciparum* antigen 332

binding protein 130

erythrocyte membrane protein 3

erythrocyte membrane protein 1

interspersed family

variable open reading frame

associated interspersed gene protein 4.2

**Protein Location Molecular** 

Erythrocyte cytoskeleton

Erythrocyte cytoskeleton

Erythrocyte cytoskeleton

Erythrocyte cytoskeleton and Maurer's clefts

Erythrocyte cytoplasm and membrane of parasitophorous vacuole

Erythrocyte cytoskeleton and Maurer's clefts

Erythrocyte membrane and Maurer's clefts

Maurer's Clefts and erythrocyte surface

Maurer's Clefts and erythrocyte surface

Maurer's Clefts and erythrocyte surface

**weight (kDa)**

85–105 Essential for the

168 It binds to the

127 Joins the spectrin.

700 Binds with the protein

274–315 Joins the spectrin.

200–250 Cytoadherence ligand,

— Possibly antigenic

— Possibly antigenic

— Possibly antigenic

actin and provides deformability of erythrocytes

105 Decrease of rigidity [48]

Interrupts the interaction of the actin-spectrin-4.1R protein complex. Involved in the trafficking of PfEMP1.

antigenic variation, and interacts with KARHP

variability

variability

variability

formation of Knobs; joins the erythrocyte spectrin, actin, and cytoplasmic tail of PfEMP-1

protein 4.1R. You can interrupt the interaction p55–4.1R

Suppresses the increase of heatinduced membrane. It can stabilize the erythrocyte membrane. Could prevent the invasion of erythrocytes parasitized

**Putative function References**

[40, 41]

[41–43]

[44–46]

[47]

[41, 49]

[50]

[38]

[51]

[52]

**54**

*Proteins from the export of P. falciparum that modify post-invasion erythrocyte [6, 9].*

Another host cell modification refers to *P. falciparum* infected erythrocyte cytoadherence to endothelial cells, resulting in a sequestration of mature parasites in capillaries and microvasculature [35]. The sequestration probably leads to microcirculation alterations and metabolic dysfunctions, which could be responsible for severe malaria manifestations [36]. The cytoadherence to endothelial cells confers at least two advantages for the parasite: (1) a more suitable microaerophilic environment for parasite metabolism and (2) evasion to splenic circulation, where infected erythrocytes would be destroyed [36–39]. *P. falciparum* exports its proteins to the erythrocyte cytoplasm, where it binds to cytoskeletal components and alters the natural interactions of the membrane structural proteins, in order to achieve these major changes in the erythrocyte structure. Export proteins are encoded by 8% of *P. falciparum* parasite genome. It corresponds to host cell exported proteins, both in asexual and gametophytic phases. **Table 1** lists the main *P. falciparum* export proteins, which participate in the remodeling process and present PEXEL motifs. However, non-PEXEL proteins such as PfEMP1, SURFIN, and Pf332 are also shown in **Table 1**, due to their importance in the infected erythrocyte remodeling process, but only PfEMP1.

## **5. Mechanism of resistance to malaria and effect of** *P. falciparum* **in erythrocyte**

Parasites of the genus *Plasmodium* have co-evolved over 200 million years with the human species [55]. In this way, the increase of migrations in multiple regions and the establishment of settlements in certain areas have influenced the increase in endemicity produced by the successive exposure of the etiological agent of the disease; this high effect of selective pressure of the parasite has co-influenced the development of genetic variations linked to endemic populations, from which they have emerged over time polymorphic variants in erythrocytes in order to respond to the most severe symptoms of the disease, hindering the survival of the parasite or preventing the development of its entire life cycle. Many of these variations may be due to changes in structural proteins of the erythrocyte, alterations in hemoglobin (thalassemia's and sickle cell anemia), or an incidence in the quantitative and functional level of enzyme activity involved in oxidative processes such as G6PD or pyruvate kinase [56, 57].

Currently, a global distribution of erythrocyte polymorphisms has been described, such as hemoglobinopathies (thalassemia's, HbS, HbC, and HbE) and enzymatic alterations such as glucose-6-phosphate dehydrogenase deficiency (G6PD), which have their origin in response to the selective pressure exerted by

malaria parasites on humans during the last 70,000 years [58]. Therefore, hemoglobinopathies and erythroenzymopathies have been attributed to different mechanisms that provide protection against severe manifestations of malaria; some of the relevant mechanisms are associated with reduced erythrocyte invasion, decreased intraerythrocytic growth, increased phagocytosis in infected erythrocytes, and increased immune response against parasitized erythrocytes [59]. Therefore, this type of erythrocyte polymorphisms can be related to resistance to malaria through immune mechanisms that can be a major health problem, due to the high frequency of carriers in endemic areas of malaria, mainly in the African continent where this It seriously affects the normal development of populations. Therefore, this type of genetic variants was originally characteristic of the tropics and subtropics; nowadays, there is a high dispersion in the whole world, product of the continuous migrations that induce an increased effect of the prevalence values of these diseases [60].

#### **5.1 Hemoglobinopathies**

Hemoglobinopathies are a group of genetic alterations that involve a change in some of the subunits of hemoglobin and present an autosomal recessive inheritance pattern [61, 62]. These are divided into structural hemoglobinopathies, produced by the simple substitution of amino acids in the α and β chains of hemoglobin and thalassemic syndromes, which are manifested by the total or partial decrease in the synthesis of a globin chain [63]. The frequency of these polymorphisms in the world population and their geographical distribution are highly variable. In the case of hemoglobinopathies, it is estimated that every year more than 300,000 children with severe forms of these diseases are born worldwide, most of them in countries of low and medium income [64, 65]. Approximately 5% of the world population carries a sickle cell or thalassemia gene, and in some regions, the percentage of carriers can reach 25%. Approximately 60–70% of all births of children with some serious alteration of hemoglobin (Hb) occurs in Africa, being the sub-Saharan region the most affected [66, 67].

#### *5.1.1 Hemoglobin S*

Hemoglobin S (HbS) is associated with a mutation in the β-globin gene where there is a change of thymine by adenine, thus coding a valine instead of glutamic acid (Glu6Val, βS). This mutation produces a hydrophobic modification in the deoxygenation of the Hb tetramer, which results in the union between the beta-1 and beta-2 chains of the two hemoglobin molecules (Hb). This union produces a polymer nucleus, which grows and invades erythrocytes, affecting architecture and flexibility and influencing cellular dehydration, with physical and oxidative cellular stress [68]. HbS is a hereditary trait that follows an autosomal recessive pattern, and therefore, it can present in a homozygous (HbSS) or heterozygous (HbAS) form. The HbSS form causes sickle cell anemia (SCA), while the heterozygote is considered a carrier of the trait [69].

It is estimated that around of 300 million people in the world, are diagnosed with sickle cell trait (SCT) a greater presence in Africa and the Mediterranean region, where the endemic areas of malaria are related to the occurrence of these hemoglobinopathies. In the United States, the prevalence of sickle cell traits is estimated at 8% for African-Americans and 0.05% for white Americans, suggesting an approximate incidence of 7.9 per 100,000 births. [70, 71].

At the metabolic level, it has been described that an increase in the production of ROS in the erythrocytes of individuals carrying the sickle trait shows a behavior similar to senescent erythrocytes. This phenomenon describes that aging causes erythrocyte cytosolic changes that affect antioxidant functioning, which can lead to the

**57**

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria*

generation of a redox imbalance and induce the hemolysis and toxic accumulation of heme and Hb in the plasma [72, 73]. This oxidative imbalance tends to be even greater in the erythrocytes of carrier individuals, a process that increases in cytosolic and membrane transformations due to the decrease in its half-life. Hence, the infection of HbAS erythrocytes with malaria parasites causes an increase in the redox imbalance associated with the metabolic activity of the pathogens. However, the molecular effects of this imbalance are not fully established and therefore it is necessary to continue with their study to establish their role in the parasitic-host relationship. Equally, have been suggested mechanisms which the sickle cell protects against malaria as shown by Pasvol et al., where an inhibition of growth of the parasite due to the polymerization of HbS and effect related with low oxygen levels is presented [74, 75]. Recently, Archer et al. demonstrated that infected erythrocytes HbAS showed a decrease in oxygen levels affecting the intracellular growth. These investigations have evidenced that growth inhibition produced by HbS-polymerized increments the cytoadherence, a condition favorable for inducing a reduction in the

Other mechanisms related have evidenced morphologic modifications in erythrocyte due to aberrant expression of PfEMP1 able of affect the binding of infected RBCs to host cells, and induce the diminution of virulence through the reduction of rosette formation and decreased cytoadherence [77]. Also, it has been described that the generation of antibodies against band-3 protein may be associated with formation of aggregated band-3 with impact in new sites for endothelium adhesion on erythrocyte with such polymorphisms and finally able cause conformational changes in band-3. Alike, it has been demonstrated that the parasite remodels the interaction of actin-cytoskeleton binding to enable the export of parasite-derived

Thus, the mechanism established that during the invasive step in sickle cell, all are affected to a phenomenon of oxidative stress. This increase in ROS induces phagocytosis phenomenon related with hemoglobin denaturation, formation and hemichrome binding, aggregation protein as band 3 protein, development of antibody and it deposition, and binding of complement C3c fragments [78]. In this way, the increase of phagocytosis processes in HbAS erythrocytes infected with *P. falciparum* is remarkably advantageous for the host, in which a succession of associated mechanisms is triggered such as growth reduction and population density of parasites, young forms of the parasite are rapidly eliminated by the immune response, and it has been observed that mature forms (trophozoites and schizonts) adhere to the endothelium in smaller proportion in important organs (lungs, kidneys, brain, bone marrow, and placenta), which has led to a decrease in the severe symptoms of the disease (cerebral malaria, placental malaria, and

On the other hand, some molecular mechanisms have been established which have included the concept of microRNA (miRNAs). The development in cultures have founded the action of two miRNAs, miR-451 and let-7i, regulating of growth of parasites. Likewise, the incidence of miR-451 and let7i have induced reduction of parasitemia and a notable effect in the incorporation of hypoxanthine producing changes in characteristic of erythrocyte and defects during invasion of parasite, which have been associated with high specificity of sequences of miRNAs with

During much time, the association between α-thalassemia and malarial protection mechanism has been studied, reporting the presence of the α + variety in the

proteins to knobs on the parasitized RBC surface [58] **Figure 3**.

*DOI: http://dx.doi.org/10.5772/intechopen.83700*

development of parasites [76].

respiratory disorders) [79, 80].

anti-parasite function.

*5.1.2 α- and β-thalassemia*

#### Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria DOI: http://dx.doi.org/10.5772/intechopen.83700*

generation of a redox imbalance and induce the hemolysis and toxic accumulation of heme and Hb in the plasma [72, 73]. This oxidative imbalance tends to be even greater in the erythrocytes of carrier individuals, a process that increases in cytosolic and membrane transformations due to the decrease in its half-life. Hence, the infection of HbAS erythrocytes with malaria parasites causes an increase in the redox imbalance associated with the metabolic activity of the pathogens. However, the molecular effects of this imbalance are not fully established and therefore it is necessary to continue with their study to establish their role in the parasitic-host relationship.

Equally, have been suggested mechanisms which the sickle cell protects against malaria as shown by Pasvol et al., where an inhibition of growth of the parasite due to the polymerization of HbS and effect related with low oxygen levels is presented [74, 75]. Recently, Archer et al. demonstrated that infected erythrocytes HbAS showed a decrease in oxygen levels affecting the intracellular growth. These investigations have evidenced that growth inhibition produced by HbS-polymerized increments the cytoadherence, a condition favorable for inducing a reduction in the development of parasites [76].

Other mechanisms related have evidenced morphologic modifications in erythrocyte due to aberrant expression of PfEMP1 able of affect the binding of infected RBCs to host cells, and induce the diminution of virulence through the reduction of rosette formation and decreased cytoadherence [77]. Also, it has been described that the generation of antibodies against band-3 protein may be associated with formation of aggregated band-3 with impact in new sites for endothelium adhesion on erythrocyte with such polymorphisms and finally able cause conformational changes in band-3. Alike, it has been demonstrated that the parasite remodels the interaction of actin-cytoskeleton binding to enable the export of parasite-derived proteins to knobs on the parasitized RBC surface [58] **Figure 3**.

Thus, the mechanism established that during the invasive step in sickle cell, all are affected to a phenomenon of oxidative stress. This increase in ROS induces phagocytosis phenomenon related with hemoglobin denaturation, formation and hemichrome binding, aggregation protein as band 3 protein, development of antibody and it deposition, and binding of complement C3c fragments [78].

In this way, the increase of phagocytosis processes in HbAS erythrocytes infected with *P. falciparum* is remarkably advantageous for the host, in which a succession of associated mechanisms is triggered such as growth reduction and population density of parasites, young forms of the parasite are rapidly eliminated by the immune response, and it has been observed that mature forms (trophozoites and schizonts) adhere to the endothelium in smaller proportion in important organs (lungs, kidneys, brain, bone marrow, and placenta), which has led to a decrease in the severe symptoms of the disease (cerebral malaria, placental malaria, and respiratory disorders) [79, 80].

On the other hand, some molecular mechanisms have been established which have included the concept of microRNA (miRNAs). The development in cultures have founded the action of two miRNAs, miR-451 and let-7i, regulating of growth of parasites. Likewise, the incidence of miR-451 and let7i have induced reduction of parasitemia and a notable effect in the incorporation of hypoxanthine producing changes in characteristic of erythrocyte and defects during invasion of parasite, which have been associated with high specificity of sequences of miRNAs with anti-parasite function.

#### *5.1.2 α- and β-thalassemia*

During much time, the association between α-thalassemia and malarial protection mechanism has been studied, reporting the presence of the α + variety in the

*Malaria*

**5.1 Hemoglobinopathies**

*5.1.1 Hemoglobin S*

ered a carrier of the trait [69].

malaria parasites on humans during the last 70,000 years [58]. Therefore, hemoglobinopathies and erythroenzymopathies have been attributed to different mechanisms that provide protection against severe manifestations of malaria; some of the relevant mechanisms are associated with reduced erythrocyte invasion, decreased intraerythrocytic growth, increased phagocytosis in infected erythrocytes, and increased immune response against parasitized erythrocytes [59]. Therefore, this type of erythrocyte polymorphisms can be related to resistance to malaria through immune mechanisms that can be a major health problem, due to the high frequency of carriers in endemic areas of malaria, mainly in the African continent where this It seriously affects the normal development of populations. Therefore, this type of genetic variants was originally characteristic of the tropics and subtropics; nowadays, there is a high dispersion in the whole world, product of the continuous migrations that induce an increased effect of the prevalence values of these diseases [60].

Hemoglobinopathies are a group of genetic alterations that involve a change in some of the subunits of hemoglobin and present an autosomal recessive inheritance pattern [61, 62]. These are divided into structural hemoglobinopathies, produced by the simple substitution of amino acids in the α and β chains of hemoglobin and thalassemic syndromes, which are manifested by the total or partial decrease in the synthesis of a globin chain [63]. The frequency of these polymorphisms in the world population and their geographical distribution are highly variable. In the case of hemoglobinopathies, it is estimated that every year more than 300,000 children with severe forms of these diseases are born worldwide, most of them in countries of low and medium income [64, 65]. Approximately 5% of the world population carries a sickle cell or thalassemia gene, and in some regions, the percentage of carriers can reach 25%. Approximately 60–70% of all births of children with some serious alteration of hemoglobin (Hb) occurs in Africa, being the sub-Saharan region the most affected [66, 67].

Hemoglobin S (HbS) is associated with a mutation in the β-globin gene where there is a change of thymine by adenine, thus coding a valine instead of glutamic acid (Glu6Val, βS). This mutation produces a hydrophobic modification in the deoxygenation of the Hb tetramer, which results in the union between the beta-1 and beta-2 chains of the two hemoglobin molecules (Hb). This union produces a polymer nucleus, which grows and invades erythrocytes, affecting architecture and flexibility and influencing cellular dehydration, with physical and oxidative cellular stress [68]. HbS is a hereditary trait that follows an autosomal recessive pattern, and therefore, it can present in a homozygous (HbSS) or heterozygous (HbAS) form. The HbSS form causes sickle cell anemia (SCA), while the heterozygote is consid-

It is estimated that around of 300 million people in the world, are diagnosed with sickle cell trait (SCT) a greater presence in Africa and the Mediterranean region, where the endemic areas of malaria are related to the occurrence of these hemoglobinopathies. In the United States, the prevalence of sickle cell traits is estimated at 8% for African-Americans and 0.05% for white Americans, suggesting

At the metabolic level, it has been described that an increase in the production of ROS in the erythrocytes of individuals carrying the sickle trait shows a behavior similar to senescent erythrocytes. This phenomenon describes that aging causes erythrocyte cytosolic changes that affect antioxidant functioning, which can lead to the

an approximate incidence of 7.9 per 100,000 births. [70, 71].

**56**

studied population [82]. The α-thalassemia is able to induce hemolytic state and be associated with a reduction in erythrocyte survival, with an increased erythrocyte in circulating young erythrocytes [83]. The α-thalassemia is very common in malaria-endemic regions; it is considered to confer protection against clinical manifestations of the disease induced by *P. falciparum*. *In vitro* studies have evidenced that in α-thalassemic erythrocytes infected with *Plasmodium*, high levels of antibodies develop from their surface. Additionally, activation mechanisms in opsonized erythrocytes, complement-induced lysis and inhibition of sequestration of infected erythrocytes have been associated, which result as anti-malarial mechanisms that might be promoted by such antibodies [84, 85].

In other studies, the roles of microcytosis have been associated with the protection from *P. falciparum*-related hemoglobin decrease; in patients, a reduction of infection for part of parasite and most notary in homozygous α-thalassemic individuals have been evidenced, where a decline of hemoglobin levels, is observed and likewise, microcytosis is related with oxidative stress induced in altered erythrocytes with the presence of thalassemia and iron-deficiency. Finally, could be linked a development of process as low resetting in infected microcytic RBCs [86]. Likewise, α-thalassemia protects against severe malaria by attenuating the effect of parasite virulence and decreasing the amount of Hb loss during increased parasitemia. The α-thalassemia erythrocytes parasitized may be more susceptible to phagocytosis in vitro culture and unavailable than normal red cells in the formation of rosettes [87, 88]. Alike, has been related the complement receptor 1 (CR1), which is reduced on α-thalassemic erythrocytes infected, the diminution of CR1 expression in this type of cells are associated with a possible mechanism for reduction resetting [89]. Following, with less able to adhere to endothelial cells. Of this mode, studies have suggested that altered cells maintain that membrane band 3 may be a target for enhanced antibody binding to parasitized a-thalassemic cells [90, 91].
