**Abstract**

Malaria is a tropical disease of parasitic origin transmitted by the Anopheles mosquito, caused by the protozoan of the genus *Plasmodium*. Around miles of people worldwide affected by disease, have been related the endemic development of genetic alterations, called erythrocyte polymorphisms. These erythrocyte polymorphisms have become tools for resistance against malaria, where they have had an impact on the appearance of hemoglobinopathies, enzymatic alterations in erythrocytes, and modifications in the structure of erythrocytes related to membrane proteins. These sections address a detailed approach to the resistance mechanisms involved against the development of *P. falciparum* and develop a complete development of the principles of molecular principles that attempt to explain the functioning of these biochemical mechanisms and the development of the parasite.

**Keywords:** malaria, *Plasmodium falciparum*, erythrocyte, polymorphism, protein, hemoglobinopathies

### **1. Introduction**

Malaria is one of the world's most severe public health problems. It leads to high rates of morbidity and mortality in many underdeveloped countries, where children and pregnant women are the most affected groups. According to the World Malaria Report by the World Health Organization (WHO), 3.5 billion people from 106 countries live in areas where they are in risk of transmission, representing half of the world's population [1]. On the other hand, malaria caused an estimated 200 million clinical episodes and 445,000 deaths, 90% of these deaths in Africa [2, 3]. Malaria is caused by parasites of the *Plasmodium* genus, which are intracellular eukaryotic organisms, with a complex life cycle. They commute between an invertebrate transmitter vector, where the sexual stages develop, and a vertebrate host, where the asexual stages take place. *P. falciparum* is responsible for the severe forms of malaria and the majority of annual deaths [4, 5].

Human malaria clinical signs and symptoms are a direct consequence of the parasite's life cycle. Humans are infected with *P. falciparum* sporozoites, through the female Anopheles mosquito's bite. Each sporozoite reaches the liver through blood or lymphatic circulation and multiplies forming a liver schizont, which differentiates into thousands of merozoites that are released into the bloodstream, after the schizont ruptures. Once released into the systemic circulation, the merozoites invade

#### **Figure 1.**

*Life cycle of Plasmodium spp. A. Exoerythrocytic cycle (1). Anopheles mosquito inoculates the sporozoites with subsequent invasion in liver cells (2); generation of first pre-erythrocytic schizogony (3). B. Erythrocytic cycle. The rupture of the schizont (4) releases the merozoites into the bloodstream where they invade red blood cells (5) forming a trophozoite that ripens into schizont, whose rupture releases merozoites back into the torrent (6). Some trophozoites can mature into gametocytes (7) that are ingested by the mosquito (8). C. Sporogonic cycle. The gametocytes mature to macrogametes and flagellated microgametes (9) that, after fertilization, produce an ooquineto (10), which migrates from the mosquito to generate oocyst (11) that will release thousands of sporozoites (12). Adapted from http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria\_il.htm.*

#### **Figure 2.**

*Merozoite invasion process in human erythrocytes. Description of invasion and internalization of the P. falciparum parasite in the host cell. (1) The nascent parasitophorous vacuole. (2) Contact closed. (A) Initial contact of merozoite to erythrocyte. (B) The adhesion of the merozoite to the erythrocyte is observed, through the specific recognition and interaction of antigens and antibodies, as well as the functional and structural role of the micronemes and rhoptries. (C) Process of invasion and development of the parasitophorous vacuole. (D) The internalization of the merozoite in the new host cell and the complete formation of the parasitophorous vacuole are detailed. Taken and adapted from Zuccala and Baum [30].*

**51**

**Figure 3.**

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

the red blood cells and initiate the intra-erythrocyte stage, which lasts approximately 48 hours. Immediately after the invasion, the growth and development staging begins first as rings (0–24 h), then as trophozoites (24–40 h), and finally as schizonts (40–48 h); the cycle ends with the host cell destruction and the release of new merozoites from circulating erythrocytes, then initiating another cycle [6] (**Figure 1**). During the development and growth stages, the parasite causes successive changes in the architecture of the infected erythrocyte (remodeling), which are fundamental for its vital functions. These changes are the acquisition of extracellular environment nutrients, the attribution of cytoadhesive properties that contribute to spleen-clearance evasion, the generation of changes in the host membrane cytoskeleton that are necessary for efficient parasite progeny release, and the formation of new organelles, such as the Maurer's clefts, tubulovesicular network, and the parasitophorous vacuole membrane (PVM) (**Figure 2**) [7, 8]. When the parasite enters the erythrocyte, it locates inside a parasitophorous vacuole (PV), which isolates it from the host cell cytoplasm, through the PVM. From then on, pathogen survival will depend on the efficient traffic

of the molecules through the PVM and the plasma membrane [4, 9].

*Mechanisms of HbAS-related protection against P. falciparum. Adapted of Bunn [81].*

**2. Human erythrocyte: properties of the human erythrocyte membrane**

The erythrocyte is a cell of approximately 8 μm in diameter, highly specialized in O2 and CO2 transportation, without a nucleus and other organelles, useful for protein synthesis. It has the ability to transit the bloodstream over a 120-days lifetime. In addition, it has a remarkable capacity for deformability that allows its movement through the capillary microcirculation and splenic endothelial clefts in approximately 1 μm diameter [10]. The erythrocyte elastic properties are due to the cytoskeleton membrane, which is formed by an array of regular hexagonal proteins which makes up a two-dimensional mesh on the cell's cytoplasmic surface. These structural proteins interact with membrane lipids to maintain fluidity and subdivide them into three protein types: cytoskeleton, integral, and anchor [11].

The membrane cytoskeleton proteins underlie just under the lipid bilayer and associate with other proteins, forming a dynamic protein network, responsible for maintaining the integrity of the erythrocyte, as it passes through narrow blood capillaries. Spectrin, actin, adducin, dematin, band 4.1, tropomyosin, and tropomodulin are within this group. Integral proteins are characterized for being embedded in the lipid bilayer and presenting intra and extracellular domains, such

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

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

the red blood cells and initiate the intra-erythrocyte stage, which lasts approximately 48 hours. Immediately after the invasion, the growth and development staging begins first as rings (0–24 h), then as trophozoites (24–40 h), and finally as schizonts (40–48 h); the cycle ends with the host cell destruction and the release of new merozoites from circulating erythrocytes, then initiating another cycle [6] (**Figure 1**).

During the development and growth stages, the parasite causes successive changes in the architecture of the infected erythrocyte (remodeling), which are fundamental for its vital functions. These changes are the acquisition of extracellular environment nutrients, the attribution of cytoadhesive properties that contribute to spleen-clearance evasion, the generation of changes in the host membrane cytoskeleton that are necessary for efficient parasite progeny release, and the formation of new organelles, such as the Maurer's clefts, tubulovesicular network, and the parasitophorous vacuole membrane (PVM) (**Figure 2**) [7, 8]. When the parasite enters the erythrocyte, it locates inside a parasitophorous vacuole (PV), which isolates it from the host cell cytoplasm, through the PVM. From then on, pathogen survival will depend on the efficient traffic of the molecules through the PVM and the plasma membrane [4, 9].

### **2. Human erythrocyte: properties of the human erythrocyte membrane**

The erythrocyte is a cell of approximately 8 μm in diameter, highly specialized in O2 and CO2 transportation, without a nucleus and other organelles, useful for protein synthesis. It has the ability to transit the bloodstream over a 120-days lifetime. In addition, it has a remarkable capacity for deformability that allows its movement through the capillary microcirculation and splenic endothelial clefts in approximately 1 μm diameter [10]. The erythrocyte elastic properties are due to the cytoskeleton membrane, which is formed by an array of regular hexagonal proteins which makes up a two-dimensional mesh on the cell's cytoplasmic surface. These structural proteins interact with membrane lipids to maintain fluidity and subdivide them into three protein types: cytoskeleton, integral, and anchor [11].

The membrane cytoskeleton proteins underlie just under the lipid bilayer and associate with other proteins, forming a dynamic protein network, responsible for maintaining the integrity of the erythrocyte, as it passes through narrow blood capillaries. Spectrin, actin, adducin, dematin, band 4.1, tropomyosin, and tropomodulin are within this group. Integral proteins are characterized for being embedded in the lipid bilayer and presenting intra and extracellular domains, such

**Figure 3.** *Mechanisms of HbAS-related protection against P. falciparum. Adapted of Bunn [81].*

*Malaria*

**Figure 1.**

**50**

**Figure 2.**

*Merozoite invasion process in human erythrocytes. Description of invasion and internalization of the P. falciparum parasite in the host cell. (1) The nascent parasitophorous vacuole. (2) Contact closed. (A) Initial contact of merozoite to erythrocyte. (B) The adhesion of the merozoite to the erythrocyte is observed, through the specific recognition and interaction of antigens and antibodies, as well as the functional and structural role of the micronemes and rhoptries. (C) Process of invasion and development of the parasitophorous vacuole. (D) The internalization of the merozoite in the new host cell and the complete formation of the parasitophorous* 

*Life cycle of Plasmodium spp. A. Exoerythrocytic cycle (1). Anopheles mosquito inoculates the sporozoites with subsequent invasion in liver cells (2); generation of first pre-erythrocytic schizogony (3). B. Erythrocytic cycle. The rupture of the schizont (4) releases the merozoites into the bloodstream where they invade red blood cells (5) forming a trophozoite that ripens into schizont, whose rupture releases merozoites back into the torrent (6). Some trophozoites can mature into gametocytes (7) that are ingested by the mosquito (8). C. Sporogonic cycle. The gametocytes mature to macrogametes and flagellated microgametes (9) that, after fertilization, produce an ooquineto (10), which migrates from the mosquito to generate oocyst (11) that will release thousands of sporozoites (12). Adapted from http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria\_il.htm.*

*vacuole are detailed. Taken and adapted from Zuccala and Baum [30].*

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 band 4.2 proteins [12, 13].
