Malaria and Host Genetics/Malaria and Molecular Aspects of the Disease

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Malaria and Host Genetics/Malaria and Molecular Aspects of the Disease

2 Introduction Malaria, recognized as one of the most severe diseases in the 21st century, is caused by the protozoan parasite Plasmodium falciparum, and is transmitted by female anopheles’ mosquitoes. It is estimated to cause the death of over 2,000,000 people among every 4,000,000 who get infected. Research has revealed that this disease is more rampant in Africa as compared to other continents (Wellems & Fairhurst 2005). It is one of the parasitic diseases whose symptoms are so severe that they can even lead to death if left untreated. Children are said to constitute the highest percentage of those affected. It is fortunate that preventive measures can be taken to minimize the number of people affected by this disease. Research has also revealed that patient’s genetic composition plays a major role in determining the severity presence of plasmodium parasites in him (Wellems et al. 2009).

This paper through qualitative analysis of legitimate sources including published work and article journals will look at the selective advantage for heterozygotes in protection against severe malaria as a consequence of the similar geographical distribution of different haemoglobinopathies. It will also describe in detail the three different types of haemoglobinopathy, in addition to outlining how combinations of haemoglobinopathies may have a negative epistatic effect in protection against severe malaria.

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3 a) Three Types of Haemoglobinopathies Hemoglobinopathies, also referred to as hemoglobin disorders, are of different types.

These are disorders characterized by abnormal hemoglobins. Some of the common hemoglobin disorders include thalassemia, sickle syndromes, and anemia. β -thalassemia Thalassaemia can in simple terms be described as a condition whereby there is defective synthesis of the globin chain. As such, there is α, as well as β-thalassemia. The genes are somehow defective and, therefore, are not in a position to produce normal hemoglobin levels.

This condition is characterized defective production of α/β globin chains (Wiwanitkit 2006). An individual can be either a carrier or infected by β -thalassemia. Homozygous individuals are said to be infected, while heterozygous individuals are said to be carriers. The carriers are protected from malaria infection. Thelassemia conditions can, therefore, be termed as genetically conferred. If a couple has mutations in the globin chains, there is the risk of getting a child who is either infected or a carrier of the involved thalassemia. Thalassemia hemoglobinopathies can be detected early during prenatal screening, and treatment is offered early such that fetal hemoglobin is able to produce non-defective globin chains. α -Thalassemia α -thalassemia is a condition characterized by impaired production of α-globin chain.

This condition is believed to present patients with protection against malarial infections.

Research has revealed that the microcytic nature of α + cells decreases their hemoglobin content and increases the likelihood of infected cells binding to protective IgG. In α -thalassemia, mild hemolysis is experienced, thus relatively more erythrocytes are found in circulation. As such, protection against malaria is not very high; mild malaria infections can occur. It is depicted that

4 α-thalassemia patients who get mild infections of malaria in early in life get better immunity against malaria due to a boost in acquired immunity thereof (Roberts & Williams 2003).

Sickle cell anemia This is a group of disorders characterized by a common feature of having one of the genes produce hemoglobin S. Sickle cell results from HBB gene mutations, thus a hemoglobin S (HBs) results. Sickle cell disease can also present in the form of a combination of HBs and othe β -chain defects. Such forms of sickle cell include sickle HbC, HbSβ +-thalasemmia, as well as HBSβ °-thalassemia (Richer & Chudley 2005). There are other variants of β-chain sickle cell, but they are rare. In sickle cell anemia, an individual inherits two genes of hemoglobin S. Under low oxygen concentration, sickle trait erythrocytes start to sickle an aspect that is believed to reduce their invasion by parasites. These cells also portray altered expression of PfEMP1 in addition to an increased rate of binding to IgG. Inheritance of sickle cell disease is through an autosomal recessive pattern. Prenatal diagnosis of sickle cell disease is available, among other newer methods involving molecular detection. b) How combinations of haemoglobinopathies may have a negative epistatic effect in protection against severe malaria Combinations of haemoglobinopathies may have a negative epistatic effect in protection against severe malaria. Epistasis can in simple terms be described as the interaction between different genes in order to control a certain phenotype. Even though recent studies have shown that people who inherit malarial-protective genetic disorders of hemoglobin are at a lower risk of being infected with this disease, it should be noted that people who inherit more than one malarial-protective genetic disorders present have a minimal level of protection against this disease (Lopez et al. 2010). In a study titled, “Negative epistasis between the malaria-protective

5 effects of α+ thalassaemia and the sickle cell trait” by Williams et al. (2005), it was revealed that malarial protection for individuals who inherit both sickle cell and α+ thalassaemia trait is far much lower when compared to the protection of those who inherited one of the traits.

This is considered a clear-cut case of negative epitasis based on the fact that while α+ thalassaemia is caused by mutation in the α+ globin, sickle cell trait is a resultant factor of beta mutation in the beta globin. This, as stated by Penman (2011), is believed to be one of the main reasons why the population of people with α+ thalassaemia is insignificant in a region where sickle cell trait is rampant.

Studies conducted over the years have revealed that the defense system of human beings and pathogenic microorganisms such as bacteria and viruses engage in constant struggle, an aspect that results either in ill health or wellbeing.

Every year, millions of people especially those living in the tropical region battle with the falciparum parasite, with the resultant factor being malaria. The human defense system and parasites engage in these battles for the sole purpose of survival. The falciparum parasite is extremely potent, necessitating the need for drugs to boost the immune system. The genetic composition of an individual has been shown to play a key role in determining the extent to which an individual will be affected by the presence of falciparum parasites (Kwiatkowski 2005).

The genetic essence of human beings resides in the DNA, which is considered the blueprint of human makeup. Each parent contributes half or 50 percent to their offspring's DNA composition. Nevertheless, there is a likelihood of spontaneous alterations occurring, implying that the genetic composition of the DNA is not a perfect melding of both parents.

6 Mutations have been shown to result in genetic conditions such as sickle cell anemia.

Even though some mutations may lead to the weakening of the immune system, some mutations have been shown to impart some survival advantage on individuals. There are genetic situations where a heterozygote for two alleles of a gene has an added advantage over the homozygous.

Research has revealed that a person with sickle cell anemia has a higher survival advantage over normal individuals when it comes to resisting malarial infection (Weatherall et al. 2002). This implies that there exists a negative selection for sickle cell disease. The actual mechanisms through which sickle cell traits impart resistance to malaria have not yet been discovered.

Reduced oxygen levels have been shown to result in the red blood cells of people with sickle cell traits attaining a sickle shape. Infestation of sickle trait red blood cells with Plasmodium falciparum parasites results in the deformation of the blood cells due to a reduction in oxygen tension within the cells (Allison 2009).

The deformed shape of the infected erythrocytes results in these cells being marked as abnormal and target to phagocytosis. The fact that selective sickling of sickle trait erythrocytes that are infected by plasmodium parasites results in a decreased burden of these parasites among sufferers increases their survival against acute malarial infections (Dzikowski & Deitsch 2009).

Some studies have revealed that the sickling effect of sickle trait erythrocytes, besides retarding the growth of plasmodium falciparum parasite may lead to their death.

Roles of PfEMP1 in Mediating Virulence in P. Falciparum Cytoadhadhesion It has been revealed that long-term infections with Plasmodium falciparum depend on antigenic variation (Dzikowski & Deitsch 2009). Plasmodium falciparum derives its virulence from the parasite-encoded protein located on the surface of mature red blood cells where it

7 resides. This surface protein is the Plasmodium falciparum erythrocyte membrane protein 1, abbreviated as PfEMP1 whose main purpose is to mediate adhesion on different host ligands.

This protein is the main red blood cells surface antigen that mediates parasites sequestration in the microvasculature. PfEMP1 is also involved in the evolution of novel adhesive characteristics displayed by a variety of plasmodium species. These proteins generate parasite induced adjustments to the erythrocyte cytoskeleton, as well as the extra-cellular features of the membrane (Smith & Craig 2005). The mechanisms through which proteins are exported to the surface of the red blood cells, however, have not yet been revealed.

Chronic infection Expression of specific variants of PfEMP1 has been shown to culminate in parasite enrichment in various tissues (Frankland 2006). This is believed to be one of the major factors in the development of chronic infections. Studies have shown that chronic malarial infections may not be direct eventualities of an adaptive virulence strategy to increase the survival capacity of parasites (Kyes et al. 2001), but rather an indication of a loss of control over the distinctively regulated process of antigenic switching whose main purpose is to maintain chronic infections (Craig & Scherf 2001). The PfEMP1 has been recognized as the main target of antibodies to the surface of erythrocytes that are infested with plasmodium parasites (Kyes et al. 2007).

Antigenic variation It has been revealed that in order for malarial parasites to complete their complex life cycle successfully, they must interact with various cells of the host organism. There are some instances where the intracellular nature of red blood cells development offers an opportunity for plasmodium parasites to be immunologically quiet (Frankland 2006). However, even in that state infected erythrocytes are present with parasite derived surface proteins. Clonal variation of these

8 proteins allows for the parasites to take on antigenic variation to allow infectivity to persist up to its transmission to a non-immune host. The encoding of this protein in parasites is done by a diverse family of var genes. The mediation of antigenic switching is carried out by clonal variation in var expression (Smith & Craig 2005). Epigenetic processes play a major role in var regulation of this encoding.

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Dzikowski, R. & Deitsch, KW. 2009. Genetics of antigenic variation in Plasmodium falciparum.

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