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Host immunogenetic and parasite mediators of anaemia in Plasmodium falciparum infection: A comprehensive review
Research investigations have revealed that protection against malaria is facilitated by host immunological and genetic factors and parasite genetics. More than a few polymorphism and hemoglobinopathies had over the lifetimes been demonstrated to influence the threat of malarial infection. This review will highpoint important features of host immunogenicity, in which astonishingly not much has been documented and which will provide essential evidence in the research for factors of malarial parasite origin that can contribute to aneamia in Plasmodium falciparum. Thus leading to the improvement of guiding principles to lessen morbidity and mortality.
Fighting against malarial infection is depicted by the development of immune response by the host and also depends on innate features having protective value against infections. Such features include ABO blood group type, sickle cell feature (HbAS), the level of G-6-Pdehydrogenase activity, sickle cell (HbSS) and type of thalassemia.
Despite intrinsic limitations of host, haemoglobinopathies and polymorphisms differ significantly in the level of immunity offered and present slight or no immunity to severe malaria and non-symptomatic parasitaemia. The prevalence of malarial parasite infection and anaemia, particularly in children under five years needs unique consideration from healthcare employees and an improved knowledge on infections is important for planning treatment guidelines.
Conversely, through lessening of the degree of pathogenicity of malaria parasites, haemoglobinopathies and polymorphisms provides a fascinating unexceptional research to assist grasp malaria’s pathogenic processes and possibly change patterns of pathogenesis and immunity into scientific use.
Keywords: Anaemia; hemoglobinopathies; polymorphisms; immunogenetic; malaria;
In sub-Saharan Africa, morbidity and mortality in children below the age of five years old is mainly caused by Plasmodium falciparum malarial infection . In most prevalent areas, although adults frequently harbor small, but appreciable parasitaemia, but hardly acquire clinical symptoms or mortality from malarial infection . Previous investigations have revealed that protection against malaria is facilitated by genetic factors and host immunological and parasite genetics [3-5]. Several hemoglobinopathies and polymorphism have over the years been shown to affect the risk of malaria that may lead to anaemia [6, 7].
Host genetic effects should be regarded as significant cause of the anaemia outbreak because these factors may have some impact on malaria vulnerability. Very often, knowledge of the associations between these polymorphisms and infection may also be limited because not many studies have been devoted on research of human genetic variants that provide some degree of immunity to or against P. falciparum infection and anaemia . The etiological effects of aneamia during malarial infection, even in these severe episodes, are multifactorial and that they might vary according to the period of the P. falciparum infection and lead to a state, which is a main cause of mortality and morbidity in children . The two major mechanisms that causes malarial aneamia are those of erythrocyte breakdown and reduced erythrocyte production .
Mostly in organs like the spleen which is involve in removing uninfected cells as a result of antibody sensitization or other physicochemical membrane variations, losing infected cells by rupture or phagocytosis and increasing reticuloendothelial activity will probably lead to hemolysis [10, 11]. Other causes of hemolysis involve dyserythropoiesis, a morphological manifestation, which in operational terms leads to inefficient erythropoiesis and reduced production lead to marrow hypoplasia observed in severe infections .
Host immunogenicity and its effect on malarial anaemia
Several different host genes are influenced by the environmental factors as they interact with parasite genetic variables and the genetic foundation of resistance or vulnerability to malaria is heterogeneous at various stages. It therefore not surprising that perhaps the substantial number of genes offering differential vulnerability to any disease has been cited for the numerous manifestations of malarial anaemia .
Over the past ten years, haplotypes based assay offer these genes a better opportunities of being selected as malaria-defensive genes distributed globally from these merging errors of metabolism like α+ thalassemia, hemoglobin S and C, and glucose-6-phosphate dehydrogenase deficiency (G6PD) . Also there is enough evidence associating polymorphisms in human genes involve in cell adhesion, inflammation, and immunity with resistance and vulnerability to malaria, hence the need to make available platforms to develop an accurate genotyping and assays .
Furthermore, among certain ethnicities, different genetic resistance factors may be more operational than others by the geographical distribution of the haemoglobinopathies and polymorphisms associated with malaria protection possibly due to differences in parasite transmission intensities that are selected for these traits as shown . Thus, the chance of an unprotected person to develop parasitaemia, the risk of a parasitaemia to cause malaria fever in a person, and the chance of an individual with malaria fever to develop severe malaria may be determine by different genetic factors . Polymorphisms in the IgG3 hinge region which results in different hinge region lengths of IgG3 has been found and appears to influence antigen specific IgG3 levels implying the polymorphs might be relevant in malaria immunity . However, the consequence of the different hinge region allotypes in clinical malaria leading to aneamia not known.
Hemoglobin which comprise the major component of erythrocytes is a tetrameric protein made of two alpha globin (the HBA1 and HBA2 genes are similarly encrypted) and two betaglobin (the HBB gene is encrypted) chains. This malaria parasite’s developmental cycle depends heavily on a hemoglobin rich environment for its success. Thus, by affecting the morphology, mechanical properties, or surface structure of the parasitized erythrocyte, modified hemoglobin may alter the biochemical and cellular machinery of parasite development, and may affect the ability of the spleen and other immune mechanisms to recognize parasites . In different populations an increase in the number of resistance against malaria is conferred by each of three different coding single nucleotide polymorphisms (SNPs) of HBB . At codon 6, glutamic acid is substituted to valine in the hemoglobin S (HbS) allele (Glu6Val) and glutamic acid is substituted to lysine in the hemoglobin C (HbC) allele (Glu6Lys), and at codon 26, glutamic acid is substituted to lysine in the hemoglobin E (HbE) allele (Glu26Lys) of the β globin chain .
Breakdown or deficiency of the hemoglobin synthesis will mostly result microcytic anaemia and iron deficiency anaemia or anaemia of chronic disease will lead to heme synthesis defect . Either alpha-, or beta-thalassemia or HbE syndrome or HbC syndrome may result in globin synthesis defect. In addition, either sideroachrestic defect or hereditary sideroachrestic anaemia or acquired sideroachrestic anaemia, including lead toxicity or reversible sideroachrestic anaemia may lead to various other unstable hemoglobin diseases .
The activities of protein are regulated during infection and against these A, B and H carbohydrate antigens of the ABO blood groups . The rhesus system blood groups consist of rhesus-positive and rhesus-negative base on the presence or absence of rhesus antigens on the surface of erythrocyte. A trial out in a Nigerian University (Igbinedion University Okada, Nigeria) confirmed that malaria parasitaemia occurred more frequently in ABO blood group O individuals  and that a higher malaria parasitaemia occurred in female than in male students. Genetic and pathogenic mechanisms described by Rowe et al.  and Fry et al.  stated that non-blood group O cases were at a higher risk of severe malaria infection. Recent findings in which pregnant women and children were tested revealed that blood group O confers more resistance to malaria infection than other blood group types [4,14], whereas blood group A has been shown to be detrimental 
Immune response to malaria
On their first exposure to the plasmodium infection, people always fall sick due to lack of former experience of malaria infection . Humans acquire feverish sickness, which may become serious and, eventually may lead to death . A quarter of all childhood mortality are due to malaria in prevalent areas and children under five years are mostly vulnerable . Sterile protection is most likely not attained, even though with exposure, juvenile and adults fundamentally develop full immunity from serious sickness and mortality . Deliberately stimulated malaria in susceptible individuals and actively immunized people in prevalent populations are the two main sources notably attributed to the protection of individuals from malaria .
Sporozoites quickly proceed from the dermis to the liver, when an infected mosquito bites through the skin and the parasites experience an asymptomatic phase of rapid mitosis before the parasites enter circulation. Feverish sickness occurs during aggressive growth of parasite populations in the circulatory system. Basically, irregular episodes of fever linked with peaks of higher parasite density during protracted infection at rather low parasitemia, while severe infection is controlled . Mostly several months of such lower density peaks, the infection is progressively eradicated. Further quicker control of continuous infections at lower parasite densities and mild or even absent clinical sickness may be demonstrated as acquisition of protection against the homologous parasite at a moderately speedy pace.
Even though a little overwhelming, clinical symptoms are also associated with early acquisition of heterologous protection in relations to parasitological indices . Both lower levels of parasitemia with age and lower incidences of disease depict protection against malaria in a prevalent area as shown in figure 1. On the other hand, the frequencies of parasitization, mild disease and severe disease have different rates of change. There may be different mechanisms underlying these distinct expressions of immunity even if it could be debated that these all indicate the same fundamental process, protection against severe malaria is principally entirely established at a time where no changes in the frequencies of mild feverish disease and when parasitemia in the population are quiet progressing. The feature that appears from human studies is that protection against malaria infection is rather slow to develop and partial, although protection against death is attained more rapidly and may be significant after a single episode .
Figure 1. The percentage of highest malarial incidence for each population index [4, 23].
Figure 1 depicts Malariainfection in a prevalent area against the population indicators of immunity . The rate of change against the different indicators of malaria in a population living in a prevalent area of P. falciparum infection: symptomless infection (pink), slight disease as a result of feverish episodes from malaria infection (blue) and acute or serious illness (green).
Mechanism and development of malarial anaemia
Several influences from host and parasite are responsible causing pathology of malaria anaemia which are also associated with its pathogenesis . Pathogenesis of acute anaemia involves various mechanisms comprising breakdown of red blood cells and phagocytic process in the spleen, increased sequestration of parasitized erythrocyte, and immune-mediated red blood cells lysis, and decrease erythroblast proliferative rates and numbers, bone marrow dyserythropoietic process and unproductive erythropoietic process . Host immunogenetic factors like, genetic makeup of diseased persons, state of pregnancy, anti-malarial immunity, local disease intensity of malaria and age may contribute relatively to anaemia through various different mechanisms. Even though, it is believed that various mechanisms are expected to function in any one individual, but dyserythropoiesis is observed in persons suffering recurrent or frequent falciparum malaria whereas, hemolysis is believed to be of enormous significance in vulnerable children experiencing severe malaria. In brief, mechanisms involve escalated destruction of non-infected and infected erythrocytes as well as a reduced production of erythrocytes may eventually lead to severe malaria aneamia (SMA) .
Removal of parasitized host erythrocytes
Reproduction by multiple asexual fission of malaria parasite occur in host erythrocytes leading to the release of merozoites and consistently causing intravascular break down of red blood cells. This may likely cause anaemia as the parasitized red blood cells undergo hemolysis. However, the dramatic fall in levels of hemoglobin normally seen in anaemic malarious children cannot only be accounted for by the breakdown of parasitized red blood cells. In children, SMA is usually correlated with parasitization that are significantly reduce than those needed for obvious, complete breakdown of erythrocytes . After malaria infestation, the surface area of the erythrocyte undergo various dramatic changes. Even though the patent lumen is much smaller in diameter, the normal erythrocytes of a mean diameter of less than 8 μm have a remarkable capacity to lengthen, permitting them to squeeze through these capillaries [28, 29]. The usually flexible biconcave disc becomes gradually more spherical and stiff and electron dense knobs emerged on the uneven surface area and as the parasitized erythrocyte matured, deformability is progressively abolished. The spleen subsequently cleared up rigid and inflexible parasitized erythrocytes held up in the splenic microvasculature, which may lead to a failure at any stage in the delivery of oxygen to cells in the tissue[29, 30]. When once parasitized red blood cells are cleared of malaria parasites, they return into circulation and this phenomenon is known as pitting, but this phenomenon has a regulatory role in malaria infection. The membrane of the once-infected erythrocytes are altered making them venerable to clearance by the stromal cells due to their more spherical and less deformability. The non-parasitized erythrocytes acquire the ring infected erythrocyte surface antigen (RESA/Pf155) as a result of the pitting of parasitized erythrocytes . Complement fixation was activated when specific auto-anti-band 3 antibodies bind band 3, a RBC transmembrane protein, known as the anion channel on the worn out erythrocyte, causing their death. The cleavage, clustering or and from exposure of cryptic epitopes resulted in an increased capacity of band 3 to specifically bind with the anti-band 3 [32, 33]. The binding of autologous IgG and complement is increased following significant changes in the membrane of the host red blood cell during the development of the malaria parasite. As a phenomenon characteristic of what may be observed with generally worn out erythrocytes, phagocytes recognize sites for deposition of autologous IgG and complement as a result of deposition of haemichromes and oxidative aggregation of band 3 due to sequential induction from the development of the parasite . Moreover, the distribution of phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is altered as the P. falciparum develop within infected erythrocyte . Macrophages readily recognize, engulf and degrade cells with exposed PS at their surface, possibly due to oxidative anxiety .
Removal of usual host erythrocytes
The main factor contributing to the inception of malarial anaemia is the destruction of many non-parasitized erythrocytes in the spleen and liver during malaria infection. The practical anaemia in malaria is caused by the destruction of usual erythrocytes as observed in both mathematical modeling and clinical studies, indicating that for every infected erythrocyte less than 13 non-parasitized erythrocytes are lost [27, 30, 37]. The escalated oxidative loss, decreased deformability of erythrocytes and externalization of PS are part of the different mechanisms that destroy non-parasitized erythrocytes, however, in addition are intravascular and extravascular hemolysis whose mechanisms remain unclear [38-40]. Severe malaria anaemia is associated with decreased deformability erythrocytes and noted as a powerful predictor of mortality in severe malarious populations [38, 39, 41]. Cell destruction by phagocytosis or complement mediated lysis result from the presence of the P. falciparum glycosylphosphatidylinositol (GPI)  on the surface of the normal erythrocytes and other mechanisms include IgG antibodies targeting parasite antigens like ring surface protein 2 (RSP-2) [43, 44]. Moreover, the host became anemic due to the destruction of membranes of non-parasitized red blood cells known as ‘guiltless onlookers’ and the malaria parasites when reactive oxygen radicals and nitric oxide are released by macrophages during malaria infection [40, 45]. The resultant severe malaria anaemia in children is due to increased oxidation of the membrane of normal erythrocytes and higher immune complexes on the surface of erythrocytes, which is associated with decreased complement receptor 1(CR1: CD35)[45, 46]. The complement activation cascade is mainly regulated by the complement regulatory protein (CRI) which prevent complement fixation in order to protect the cells .
Reduced production of erythrocytes
In the bone marrow, decreased production of red blood cells significantly causes anaemia, which normally takes almost a month to resolve, even though destruction of erythrocytes during severe malaria infection also leads to anaemia. Unsuitably minimal amount of erythropoietin, dyserythropoiesis and inefficient erythropoiesis and bone marrow hypoplasia/suppression, dyserythropoiesis are mainly caused by reduced red blood cell production . Throughout usual homeostasis, the number of erythrocytes are well-adjusted between senescent erythrocyte damage by the reticulo-endothelial system (RES) and fresh erythrocyte production through erythropoiesis as the erythrocytes generally remain in circulation for almost four months In bone marrow or spleen, haematopoietic stem cells under the influence of erythropoietin reproduce and differentiate into reticulocytes and these premature erythrocytes are release into circulation and effective erythropoiesis is known as the capability of the bone marrow to counterbalance for unexpected rise in erythrocytes deficit . During malaria infection, accelerated clearance of red blood cells is not counter balanced by sufficient bone marrow response resulting in less reticulocyte count which reflects a decreased bone marrow productivity to replace the erythrocyte deficits and this process certainly develops into anaemia.
In malarial anaemia, bone marrow suppression has been described in all malaria patients as well as in asymptomatic infections , and is thought to be responsible for both the degree of and the delayed recovery from anaemia . In acute malaria, there is a reduced total erythropoietic activity, as indicated by a normal or reduced marrow cellularity combined with reduced erythroblast proportions. Meanwhile, in chronic malaria, there is an increase in total erythropoietic activity, as evidenced by an increase in marrow cellularity (erythroid hyperplasia) together with an increased proportion of erythroblasts accompanied by inappropriately low levels of reticulocytosis, suggesting that this is associated with a greater ineffectiveness of erythropoiesis than in acute malaria [25, 47]. In addition, RBC iron utilisation, a measure of effective erythropoiesis is reduced in both acute and chronic malaria. It is thought that during malaria infection, there is a shift of iron distribution from functional compartments, comprising metabolically active iron that is required for normal function, toward storage compartments, that constitute an iron reserve, and thus suggesting a relative deficit in erythropoietin production or bone marrow unresponsiveness to erythropoietin . Functional studies on dyserythropoietic bone marrows confirmed that there was an abnormal cell cycle distribution of early polychromatic erythroblasts in both acute and chronic malaria, with an increased proportion of cells in the G2 phase of the cell cycle, and a reduction in the ratio of the number of cells in the DNA synthesis (S) phase to the number in G2 (S/G2 ratio) . Further kinetic studies of erythroblasts suggested that all classes of erythroblasts had a prolonged S phase and the rate of production of polychromatic erythroblasts was reduced by about 50% of normal and this was thought to be as a result of a high death rate in this cell compartment . Based on morphological abnormalities of erythroblasts in the bone marrow of patients, the basis for the ineffective erythropoiesis was thought to be due to apoptosis . Morphological abnormalities of erythropoiesis (dyserythropoiesis) include multi-nucleated erythroblasts, rupture of the cell nucleus with disintegration of chromatin (karryorrhexis), as well as incomplete mitosis. In a study of Gambian children with malaria, the disturbance in erythropoiesis was found to be confined to the morphologically recognisable erythroblast population (early polychromatic erythroblasts). The prevalence of these abnormalities was more marked in children with chronic than acute malaria [25, 47]. The mechanisms underlying the perturbation of erythropoiesis and ineffective erythropoiesis are not fully clarified. Several factors have however been implicated including direct and indirect effects of factors produced by the parasite.
Effect of soluble mediators (cytokines /chemokines)
Following clinical observations, the nature of the host’s response critically influences the
pathologic manifestations of malaria infection. Severe malaria is known to be associated with an acute inflammatory response characterized by elevated levels of pro-inflammatory cytokines and elevated responses have been linked to the etiology of severe malarial anaemia [55, 56]. The macrophage migration inhibitory factor (MIF) is produced by activated T cells and macrophages, and has a wide range of biological activities including the induction of tumour necrosis factor alpha (TNF-α). MIF also stops the anti-inflamatory activity of glucocorticoids and it is released from macrophages in response to Plasmodium infected red cells. Due to its prominent expression in plasma, spleen and bone marrow during experimental malaria, it has been implicated in the development of malarial anaemia through erythropoietic suppression [57, 58]. In in vitro studies, MIF was found to inhibit the formation of burst forming unit-erythroid (BFU-E) cells . MIF-knockout mice infected with P. chabaudi developed less severe anaemia had better erythroid development (as evidenced by increases in colony forming unit-erythroid (CFU-E) and BFU-E and demonstrated an improved survival relative to controls .
Tumour necrosis factor (TNF-α) is an important immunoregulatory molecule in malaria which on one hand plays an important role in limiting malaria parasitaemia; but on the other hand is responsible for the development of the life-threatening complications of severe malaria. In patients with malarial anaemia high levels of serum TNF have been reported which were correlated with the severity of the anaemia . Children with severe anaemia were observed to have a depressed reticulocyte response and gross morphologic abnormalities of erythropoietic cells in the bone marrow. In rheumatoid arthritis patients an increased local production of TNF-α is associated with a low frequency and increased apoptosis of bone marrow erythroid progenitor and precursor cells, and the cytokine is responsible for the anaemia seen in these patients . The chemokine Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES: CCL5), has been implicated in malarial anaemia. Known functions of RANTES include promotion of the migration of erythroid precursors into hematopoietic tissues as well as prevention of erythroid progenitor cell apoptosis and suppression of RANTES may lead to an ineffective erythropoietic response. In a study of Kenyan children, RANTES was observed to decrease during severe malaria anaemia and was associated with the suppression of erythropoiesis .
During infection, the concentration of hemozoin (Hz) after erythrocyte rupture may be as high as 100 μg/ml, but it is rapidly cleared from the circulation by the liver and spleen because of its particulate nature. As a result of its high concentration in immune tissue, Hz has been suggested to contribute to the systemic inflammatory immune responses seen during malaria infection. It has been shown that Hz purified from P. falciparum activates macrophages to produce pro-inflammatory cytokines, chemokines, and nitric oxide as well as enhance maturation of human myeloid dendritic cells (DC) [63, 64]. In a study of Kenyan children with malaria, circulating free and intraleukocytic Hz was found to be associated with anaemia and ineffective erythropoiesis, probably as a consequence of lipid peroxidation . Furthermore, this association was independent of levels of the proinflammatory cytokines TNF-α and IFN-γ which have also been implicated in the suppression of erythropoiesis during anaemia . In vitro, 4-hydroxynonenal (4-HNE), a final product of lipid peroxidation generated by hemozoin was found to inhibit the growth of progenitor erythroid cultures. Thus, 4-HNE, in addition to playing a role in erythrocyte deformability and consequent cell destruction, may also be involved in dyserythropoiesis and anaemia .
The spleen and reticuloendothelial hyperactivity
The spleen plays a very important role in the pathophysiology of malaria. One of its functions is in the removal of infected, opsonised or damaged cells in the circulation . This operation by the spleen reduces the amount of erythrocytes from circulation and thereby resulting in anemic condition especially in children. A rapid splenic enlargement in malaria has been associated with its increased capacity to clear both damaged and infected red cells from the circulation, both by Fc-receptor mediated immune mechanisms and by recognition of the reduced deformability, thus limiting the acute expansion of infection. In addition, splenomegaly has been associated with macrophage hyperplasia during malaria .
Concluding remarks and future perspectives
Until P. falciparum is eradicated, the goal must be to reduce the incidence of the disease. The findings on the prevalence of malaria infection and anaemia, particularly in children under five years requires special attention from healthcare personnel and better understanding of the pathogenesis of malarial infection is crucial for designing treatment strategies. However, through reduction of the virulence of malaria parasites, haemoglobinopathies and polymorphisms provides an attractive usual experiment to help understand malaria’s pathogenic mechanisms and potentially transform models of pathogenesis and immunity into clinical application. Despite intrinsic limitations of all these studies, haemoglobinopathies and polymorphisms differ significantly in the level of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia.
Responsibility of the funders
The funders of this study have no role in study design, data collection, data analysis, data interpretation, or writing of the article. The corresponding author had complete access to all the data in the study and absolute obligation for the decision to submit for publication.
KT designed and conceived this study, search for literature, analysed and interpreted data, and scripted the article. BA and FA conceived and designed the study, and supervised the study. KT had complete access to all of the data in the study and is accountable for the reliability of the data and the precision of the data analysis.
KT, BA and FA are grateful to study subjects and researchers of the primary studies. They thankfully acknowledge the anonymous reviewers and editors for the comments and valuable inputs to enhance the value of our manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
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