How do sickle cells prevent malaria

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All authors reviewed the final manuscript and agreed for submission. All authors read and approved the final manuscript. Correspondence to Claude Ngwayu Nkfusai. These blood cells explode, releasing parasites capable of infecting other red blood cells. The parasite triggers the SCT hemoglobin to sickle. The immune system then clears the infected red blood cells before the parasite can complete its life cycle and infect other red blood cells.

This means fewer parasites and milder illness. The places where malaria is most common are also the places that have the highest percentage of people with SCT. This is not by accident. Malaria is so deadly that the body came up with a way to fight it. By changing the genetic code of hemoglobin and causing SCT, the carrier has a better chance of surviving a disease with a high death rate.

Having sickle cell trait provides malarial protection, but having sickle cell anemia HbSS does not. A study of children in Kenya between 16 months and 2 years old showed that those with HbSS had the lowest chance of surviving malaria. However, kids with SCT had the highest chance of survival. Survival rates for those with normal hemoglobin were between those with sickle cell trait and HbSS.

It seems illogical that SCT would continue to spread when it can cause sickle cell disease. SCT is an example of balanced polymorphism. This is when a genetic change is both good and bad.

In this case, the good is protection against malaria. The bad is the chance of 2 people passing SCT genes to their child who will then have sickle cell disease. SCT came from places where malaria is the main cause of death, so anything that provides protection has a good chance of being passed on.

However, in places where malaria is not a threat, having SCT is not helpful. It leads to sickle cell disease, which lowers life expectancy and causes major health problems. By providing your email address, you are agreeing to our privacy policy. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Malaria, especially that caused by Plasmodium falciparum , has been a major cause of morbidity and mortality throughout human history. As a result, malaria has exerted extraordinary evolutionary pressure on the human genome and appears to have selected for multiple genetic polymorphisms that provide protection against severe disease [ 1 — 4 ]. The best-characterized human genetic polymorphism associated with malaria results in sickle haemoglobin HbS.

The high prevalence of HbS in sub-Saharan Africa and some other tropical areas is almost certainly due to the protection against malaria afforded to heterozygotes [ 1 — 3 , 5 ]. Since the protective effect of sickle cell trait on malaria was first described over 60 years ago [ 6 — 8 ] our understanding of the epidemiology and mechanisms of protection of this genotype have continued to expand, as will be discussed below.

Sickle haemoglobin HbS is a structural variant of normal adult haemoglobin. Adult haemoglobin HbAA is made up of two alpha and two beta globin chains. Homozygotes for haemoglobin S HbSS with two affected beta chains develop sickle cell disease, in which polymerized haemoglobin causes red blood cells to sickle and occlude blood vessels.

Vaso-occlusion affects many organs and tissues, and results in high morbidity and mortality. Heterozygotes for sickle haemoglobin HbAS have sickle cell trait and are generally asymptomatic [ 10 ]. Despite the obvious deleterious nature of HbSS, it is now widely accepted that the persistence of the sickle mutation in human populations is due to the protection from malaria afforded to heterozygous individuals. Haldane first proposed the concept of a heterozygote advantage against malaria in [ 11 ].

In this seminal paper, Haldane suggested that individuals heterozygous for thalassaemia, another haemoglobinopathy, were protected against malaria. Contemporaneous to this hypothesis, epidemiologic evidence for protection against malaria in those with HbS was emerging.

This study showed a reduced prevalence of parasitaemia particularly P. Since these observations, strong evidence for the protective effects of HbAS against malaria has been generated in multiple case control and cohort studies [ 12 — 17 ].

Recently, an evidence-based map of the global distribution of the sickle cell variant has been created in a bayesian geostatistical framework and compared to the global prevalence of P. These data provide comprehensive evidence for a global geographical association between malaria burden and HbS allele frequency, particularly in sub-Saharan Africa.

Furthermore, evidence for the protective effects of other red blood cell polymorphisms against malaria, including haemoglobin C, haemoglobin E, thalassaemias, and ovalocytosis have also been described [ 17 — 28 ].

In endemic countries, infection with P. HbAS provides significant protection against both severe and uncomplicated malaria. While associations between HbAS and protection against malaria are clear, data from clinical studies aiming to identify mechanism s of protection have been less consistent.

Older studies found a lower prevalence of parasitaemia in HbAS individuals irrespective of symptoms [ 7 , 37 ], suggesting HbAS exerts protection against the establishment of parasitaemia. Multiple other reports failed to identify an association between HbAS and the prevalence of asymptomatic parasitaemia [ 29 , 31 , 38 — 40 ], but three recent studies found that HbAS children had significantly less asymptomatic parasitaemia than HbAA children [ 41 — 43 ].

Further, HbAS children in Ghana had significantly lower parasite densities and a higher proportion of submicroscopic P. Data on associations between HbAS and the multiplicity of infection, the number of genetically distinct parasites causing an infection, are limited and results have been conflicting [ 26 , 35 , 44 , 45 ].

To further investigate the effect of HbAS on parasitaemia, another study followed a cohort of Ugandan children aged one to ten years for asymptomatic parasitaemia and symptomatic malaria, using genotyping to detect and follow individual parasite clones longitudinally [ 35 ]. This study found that HbAS protected against the establishment of parasitaemia by decreasing the force of infection, or the average number of parasite strains causing blood stream infections, and the probability of developing clinical symptoms once parasitaemic.

HbAS children were also protected against high parasite densities during symptomatic malaria, consistent with prior studies [ 26 , 29 — 31 , 33 , 35 , 41 , 46 ], likely contributing importantly to protection against severe malaria. These discrepancies suggest that the mechanism of protection afforded by HbAS is complex, with impacts on both the development of parasitaemia and the control of parasitaemia once it is established. Some decades ago, investigators found that P.

In the s, two groups showed that parasitized HbAS cells sickled at a two to eight times higher rate than non-parasitized cells [ 47 , 48 ]. One group also visualized polymerized haemoglobin in parasitized red blood cells and hypothesized that an increase in the polymerized haemoglobin or a reduced intracellular pH might cause increased sickling [ 48 ].

Increased sickling of parasitized red blood cells in HbAS individuals may promote enhanced phagocytosis of infected cells and, therefore, result in reduced parasitaemia compared to that in HbAA individuals Table 1. Later in the s, multiple studies found that P. Parasite growth was inhibited in both sickled and non-sickled HbAS red blood cells [ 50 ] suggesting that factors in addition to sickling affected parasite growth.

It has been hypothesized that specific intra-erythrocytic conditions of HbAS red blood cells, such as low intracellular potassium [ 49 ], high concentrations of haemoglobin [ 51 ] or osmotic shrinkage of the red blood cell [ 52 ] cause an inhospitable environment for parasites. A study also demonstrated that P. Recent data provide support for the intriguing possibility that human micro RNAs translocated into parasite mRNA reduce intra-erythrocytic growth. This study found two human micro RNAs that were highly enriched in erythrocytes with HbAS, and these micro RNAs inhibited translation of specific parasite mRNA transcripts negatively impacting parasite growth in vitro [ 54 ].

Biochemical and mechanical changes in infected HbAS red blood cells have been shown to alter disease progression. Rosette formation, which is the binding of P. Rosette formation was found to be impaired in P. Impaired rosette formation with HbAS red blood cells may be due to increased sickling of these cells in deoxygenated conditions [ 47 , 48 ] or to reduced expression of erythrocyte surface adherence proteins [ 60 ].

Decreased rosette formation and the resulting decreased circulatory obstruction might contribute to protection against severe malaria in HbAS individuals. Reduced cytoadherence has also been implicated as a mechanism of protection in HbAS individuals. Infected red blood cells express one of a family of parasite-encoded P. This process, termed cytoadherence, enables parasites to sequester in the vasculature and avoid clearance by the spleen [ 64 ].

Cytoadherence also leads to endothelial activation and associated inflammation in the brain and other organs, important in the progression to severe malaria [ 65 — 68 ]. Comparison of binding properties showed reduced adherence to endothelial cells expressing the binding ligand CD36 compared to HbAA red blood cells. In addition, dysfunctional cytoskeletons have been visualized in HbSC erythrocytes [ 70 ]. Oxidized haemoglobin present in erythrocytes containing sickled haemoglobin may interfere with actin re-organization in infected HbSC erythrocytes leading to impaired vesicular transport of PfEMP-1 to the erythrocyte surface membrane [ 70 ].

These changes may impair parasite-induced remodelling of the red blood cell surface membrane and lead to altered PfEMP-1 surface expression [ 60 , 69 ]. Reduced cytoadherence of HbAS and HbSS erythrocytes likely leads to increased splenic clearance, and may in part explain lower parasite densities and a lower incidence of severe malaria in HbAS individuals.

Phagocytosis by monocytes of HbAS red blood cells infected with ring-stage P. Enhanced phagocytosis may be due to increased presentation of opsonins, including membrane bound IgG, C3c, membrane-bound hemichromes, and aggregated band 3 [ 53 ]. These opsonins, which are thought to be involved in the removal of senescent red blood cells, were first shown to be increased in G6PD deficiency [ 71 , 72 ], a red blood cell enzyme deficiency also protective against malaria [ 1 ] and were also significantly higher in infected HbAS compared to HbAA red blood cells.

Clearance by monocytes of red blood cells with exposed phosphatidylserine, a surface marker of damaged erythrocytes [ 73 — 77 ], was also enhanced in infected HbAS compared to HbAA cells [ 73 ]. Enhanced opsonization and clearance of parasitized HbAS red blood cells by the spleen may lead to increased antigen presentation and earlier development of acquired immunity compared to that in HbAA individuals. A cross-sectional study found decreased levels of peripheral myeloid dendritic cells and monocytes in individuals with HbAS during healthy periods and malaria [ 78 ], suggesting increased monocyte and dendritic cell recruitment to the spleen.

Population studies have found that the protective effect of HbAS increases with age, suggesting an acquired component of protection. A cross-sectional study of children with malaria in Nigeria found a significantly lower mean parasite density in HbAS compared with HbAA children in those two to four years old, but not in children less than two years old [].

In a recent study, protection against the establishment of parasitaemia and the development of symptomatic malaria once parasitaemic significantly increased between the ages of two and nine years [ 35 ]. Several studies shed light on possible immune bases for acquired protection. Cell mediated responses to P. The mean lymphoproliferative response to affinity-purified P. Thus, available results suggest a more robust cellular response to P. However, it is unclear whether this is a cause or effect of the protective effects of HbAS.

The lymphoproliferative response is suppressed during and after acute malarial infection in HbAA individuals [ 64 , 81 , 86 — 89 ]. Therefore, a more robust lymphoproliferative response in HbAS individuals could be secondary to protection against malaria from other mechanisms.