*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria DOI: http://dx.doi.org/10.5772/intechopen.93807*

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

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

#### **Figure 2.**

gradually highlighted and established especially in South East Asia and in Latin

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].

*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].*

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

America [2, 14–16].

**Figure 1.**

**8**

been extensively documented [12].

*Human Blood Group Systems and Haemoglobinopathies*

*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.*

2.Those in which there is a qualitative disorders of globin structure defect in one

• Sickle cell disorders: Sickle Cell trait, Sickle cell anemia disease, SC

• Hemoglobin with decreased stability (unstable hemoglobin variants):

• fetal hemoglobin (HbF), the main hemoglobin in the fetal period which

• adult hemoglobin (HbA), which increases after birth up to more than 96% of total hemoglobin, has two α and two β chains (α2β2).

Human Hemoglobin genes are located in the α-globin and β-globin gene clusters in chromosomes 16 and 11. Due to spontaneous mutation, hemoglobin gene variants

They fall into two broad groups structural variants that change the amino acid sequence and produce an unusual hemoglobin, [8] and thalassaemias that lower or

Morbidity and mortality rates from SCD and β-thalassemia are still very high and represent an important challenge. Increased understanding of pathophysiological aspects has lead to significant improvements in the treatment and prevention of these diseases [25]. However most hemoglobin gene variants are rare and many are harmless, but some are common because carriers are less likely than others to die

We are interested in inherited hemoglobin disorders that are common enough to

SCD is a group of inherited RBC disorders; it is by far the most common IDH worldwide. SCD is caused by a variation in the gene that codes for hemoglobin, the protein in our red blood cells that helps carry oxygen to all parts of the body. The altered protein found in people with SCD is called hemoglobin S and occurs in people who have inherited the hemoglobin S (HbS), the red blood cells become hard

**Hemoglobin S** results from an amino acid substitution at the sixth residue of the β-globin subunit: β6-Glu ! Val. RBCs of persons with HbAS typically have 40% HbS and 56–58% HbA [24]. The frequency of allele S is up to 0.2 in some parts of sub-Saharan Africa [26–28]. In equatorial Africa, where malaria is endemic, the prevalence of HbAS is much higher and can reach over 30% in some populations because of the survival advantage of HbAS heterozygotes from complications of *P. falciparum* malaria. Individuals with HbAS are typically asymptomatic; severe hypoxia is required for them to experience manifestations of SCD, called sickling. Persons who have inherited the HbS gene from only one parent are Heterozygote for the Sickle gene (AS). They carry the gene certainly, but they usually do not have the disease and are more tolerant of malaria infection, making them more

SCD is most common in Africa where limited resources and these resources carefully targeted are often directed towards sectors other than health. However, it

be of public health significance and particularly in those with a link to malaria.

of the globin subunits: Structural variant of hemoglobin

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

has two alpha (α) and two gamma (γ) chains (a2γ2),

are present at low prevalence in all sizeable populations [5].

disease, sickle β-thalassemia disease

G6PD deficiency Hemoglobin includes four globin chains:

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

abolish production of globin chains [12].

from *falciparum* malaria.

*2.2.1 Sickle cell disorders*

likely to survive the disease [12, 29].

and sticky [12].

**11**

**Figure 3.**

*Representation of the blood-stage of* P. falciparum *life cycle in the human host and the malaria-protective variants that have important roles in the red blood cell (RBC). Image adapted from [1].*
