**2. Inherited disorders of hemoglobin (IDH) and** *Plasmodium falciparum (P. falciparum)* **malaria**

#### **2.1 Brief review of malaria infection**

Malaria is a severe infectious disease caused by parasites of the genus *Plasmodium*. *Plasmodium* is one of the longest-known parasites, which are transmitted to humans by a bite of an infected female mosquito of the species Anopheles.

Indeed, after inoculation into a human by a mosquito, the *P. falciparum* parasites enter the erythrocytic stage of their life cycle after a brief silent incubation in life (**Figure 2**). It is during this time that parasites sequentially invade and egress from their host RBCs and cause the signs and symptoms of malaria. Hemoglobin is the oxygen - carrying component and major protein of the RBC [11]. Indeed, the RBC is essential for the spread of malaria parasites, as summarized in **Figures 2** and **3**.

Despite progress towards its control of malaria, it is still the most important parasitic disease and then, one of the world's worst health problems. In 2018, about 228 million cases of malaria occurred worldwide. Most of these cases (93%) occurred in African Africa region In the same year malaria was responsible for 405 000 deaths made up to 67% (272000) of children under 5 years recognized as the most vulnerable group [12]. However, early diagnosis and fast-acting treatment prevent unwanted outcomes. Until recently it was thought that only four species of malarial parasite (Plasmodium) especially *Plasmodium. falciparum (P. falciparum), Plasmodium.vivax (P.vivax), Plasmodium. malariae (P.malariae), and Plasmoduim. ovale (P.ovale)*, have humans as their natural hosts. But, it has been found that many cases of malaria that were previously diagnosed as being due to P. malariae infection are in fact due to a fifth parasite, *Plasmodium. knowlesi (P. knowlesi)* mostly in Malaysia [13].

It has long been thought that *P. falciparum* was the only cause of severe malaria cases and deaths, until the equally destructive, if not worse, the role of *P. vivax* is

**Gene** 

**6**

**(chromosome)**

 **Mutation**

**Change**

C (HbC)

 Glu6Lys

2

HbC alleles protect against

uncomplicated

malaria.

 malaria and severe

GAG/AAG

 **Number**

**Protein Function**

 **Reported Genetic** 

**with Malaria**

**Associations**

**Mechanistic**

**Proposed protective mechanism**

parasite growth due to oxygen-

dependent Increased immune clearance of infected

erythrocytes

Impairment

invasion and growth under conditions of

low oxygen tension [31, 43, 47]

Improved acquisition of

immunity [33, 47, 58]

Reduced infected red blood cells because of reduced expression of PfEMP1 [33, 64,

65] and Reduced

infected erythrocyte increased immune clearance of infected

erythrocytes

Impairment

invasion and growth [75].

AE

protection from invasion into

erythrocytes

[53, 73]. Reduced erythrocyte

merozoites,

parasite growth, and enhanced

phagocytosis

[22, 75].

 *location, the mutations, the protein, function and also the reported*

 *about them, including their chromosomal*

*Note: The variants at the β- and α-globin loci that confer resistance to malaria and information*

*Genetic Associations*

**Table 1.** *Common erythrocyte*

 *variants that affect* 

*susceptibility*

 *and resistance to* P. falciparum

*malaria.*

 *with Malaria, Mechanistic*

 *hypotheses and finally their distribution.*

 of infected

erythrocytes

 lower

 invasion by intra-erythrocytic

 by *P. falciparum*

malaria

heterozygotes

 appear to have

 of *P. falciparum* red cell

Southeast Asia 0.7

E (HbE)

 Glu26Lys

1–3

HbE allele reduces parasite invasion

and protects against severe malaria.

GAG to

AAG

 [22, 29]

 [23]

cyto-adherence

 of

pathogenicity

 of P. falciparum

malaria-specific

*Human Blood Group Systems and Haemoglobinopathies*

 of *P. falciparum* red cell

 [29, 35]

polymerization

 of HbS [30]. West Africa

 0.5

 **hypotheses**

**Distribution**

 **High** **Frequency** gradually highlighted and established especially in South East Asia and in Latin America [2, 14–16].

*P. falciparum* malaria is a major cause of mortality and morbidity, particularly in endemic areas of sub-Saharan Africa [2, 20]. Indeed the disease etiology is variable and is attributable to environmental factors, parasite virulence and mostly host genetics [21]. Variations in the severity of *P. falciparum* infections considered as different phenotypes include parasitaemia (hyperactive or asymptomatic), severe malaria anemia and cerebral malaria. Host genetic factors contribute to the variability of malaria phenotypes [22] and thus, should help to determine some of the mechanisms involved in susceptibility to *P. falciparum* infection. Some authors have summarized common mechanisms by which hemoglobinopathies may

The knowledge gained with several studies has produced undisputed evidence about polymorphisms associated with malaria resistance. Indeed, several gene mutations and polymorphisms in the human hosts confer survival advantage and have increased in frequency through natural selection over generations. These include the classical polymorphisms that cause Sickle Cell Disorders (SCD) and haemoglobinopathies such as α-thalassaemias and G6PD deficiency and the major RCB group variants [23]. However, with news technology and experimental design, other polymorphisms have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and some

*Common mechanisms by which hemoglobinopathies may attenuate the pathogenesis of* P. falciparum *malaria. (A) Restriction of RBC invasion or intraerythrocytic growth, thereby suppressing parasite densities in Vivo; (B) Interference with parasite-derived mediators of pathogenesis, including those involved in the binding of parasite-infected RBCs to extracellular host receptors; (C) Modulation of innate host defenses to favor protective, anti-inflammatory responses over those that drive pathogenic, pro-inflammatory responses; (D) Enhancement of adaptive cell-mediated and humoral immune responses that clear iRBCs from the blood. Source: Taylor SM, Cerami C, Fairhurst RM (2013) Hemoglobinopathies: Slicing the Gordian Knot of Plasmodium falciparum Malaria Pathogenesis. PLOS Pathogens 9(5): e1003327. https://doi.org/10.1371/journal.ppat.1003327. https://*

*journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003327.*

attenuate the pathogenesis of *P. falciparum* malaria (**Figure 2**) [11].

*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria*

*DOI: http://dx.doi.org/10.5772/intechopen.93807*

variants related to the immune response (**Figure 3**) [10].

**Figure 2.**

**9**

Regarding the relationship between the severity of malaria and host genetics, it appears that *P. falciparum* malaria is one of the deadly forms of malaria with a life cycle including alternatives hosts: a sexual cycle in the insect vector, an Anopheles mosquito, and a human cycle in a liver stage and an erythrocyte stage. However, the resistance mechanisms have been described in the sporozoite entry to liver cells and in the erythrocyte invasion by merozoites (**Figures 1** and **3**) [17, 18]. Genetically based resistance is involved in either altering erythrocyte invasion by merozoites, in lowering parasite growth or in impairing merozoite viability after being released from schizonts [17, 19]. The genetic resistance in the blood stage step has been extensively documented [12].

There are multiple points in the parasite lifecycle that have impacted host genetic variation, but the majority of the malaria-protective variants described so far have various important impacts on the structure and function of the RBC [2].

#### **Figure 1.**

*The life cycle of the malaria parasite (schematic diagram illustrating life cycles of* P. falciparum*, involving Anopheles mosquito and human hosts). Adapted from: Figure from Lopez et al. (2010). [Lopez C, Saravia C, Gomez A, Hoebeke J, Patarroyo MA: Mechanisms of genetically-based resistance to malaria. Gene 2010, 467:1–12.] and lee et al.(2019) [Wenn-Chyau lee, Bruce Russell, Laurent Rénia sticking for a cause: The falciparum Malaria parasites Cytoadherence paradigm immu.2019.01444].*
