How Sickle Cell Trait Protects Against Malaria ?

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By Dr.Syed K.Haque

A child dies of malaria every 30 seconds.  Sounds scary?  But this is no joke.   It’s true.   In 2006 alone, there were 247 million cases of Malaria worldwide.  Of this nearly one million died, most of whom were African Children (WHO Factsheet).  Females are not as innocuous as they look (wink).  The female anopheles mosquito is the most deadly of the four types.It causes falciparum malaria.

Some basic information about malaria will help in enjoying this article to the fullest.  So go through this short, 3D educational animation on the life cycle of the malarial parasite.


Courtsey :Steve Swank , MD
Another very good one from Howard Hugh Medical Institute is here.

What is sickle cell disease ?
Haemoglobin, a metalloprotein in red blood cells, consists of four polypeptide chains.  Haemoglobin has several variants.  Haemoglobin S is the variant seen in sickle-cell disease.  It results from a point mutation in the β-globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.  The red blood cell with this kind of haemoglobin changes shape under hypoxic condition from a smooth, donut-shape to a sickle shape.  The sickle cell blocks small blood vessels leading to various signs and symptoms.

For more detailed information on sickle haemoglobinopathies watch the following video.



Now, how did we come to know of the protection that sickle cell trait offers against malaria? An interesting observation made by epidemiologists that the geographical distribution of the gene for hemoglobin S (sickle cell) and the distribution of malaria in Africa virtually overlapped, triggered a barrage of research.  This research confirmed sickle cells' protectitive traits.  The gene for sickle cell survived as a result of natural selection.  The interesting aspect is that the sickle cell disease becomes deadly when malaria inflicts but the acquired traits help to purge malarial parasites.

Sickle cell trait provides a survival advantage over people with normal hemoglobin in regions where malaria is endemic, and it provides neither absolute protection nor invulnerability to the disease.  Rather, people (and particularly children) infected with P. falciparum are more likely to survive the acute illness if they have a sickle cell trait.  When these people reproduce, both the gene for normal hemoglobin and that for sickle hemoglobin are transmitted into the next generation.

The exact mechanism of resistance to malaria is unknown.  Several elements are possibly involved and add in to the defense against malaria.

Sickling does not occur with sickle trait at normal venous oxygen tension.  But very low oxygen tensions, such as extreme exercise at high altitude (Martin, et al., 1989), will cause the cells to sickle in people with sickle cell trait.  When malarial parasite P.falciparum infects Sickle trait red cells, sickling takes place.  The reason forwarded is that the metabolism of the parasite lowers the oxygen tension within the erythrocytes resulting in sickling.  Deformed sickle trait erythrocytes are engulfed and destroyed  by phagocytes (Luzzatto, et al., 1970).

In vitro experiments with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle at a faster rate than do uninfected cells (Roth Jr., et al., 1978).  Destruction of sickle cells, which takes place in the reticuloendothelial system, clears up the parasite alongside.  These people, in contrast to the ones without or with two Haemoglobin S allele, have an advantage in survival through an acute malarial infections.

Other researches point to an increased oxygen radicals in sickle trait erythrocytes.  This possibly eliminates the P. falciparum parasites (Anastasi, 1984).  Sickle trait red cells produce higher levels of the superoxide anion (O2-) and hydrogen peroxide (H2O2) than do normal erythrocytes.  These are lethal to several pathogens, even malarial parasites.  Homozygous hemoglobin S red cells produce membrane associated hemin secondary to repeated formation of sickle hemoglobin polymers.  This membrane-associated hemin can oxidize membrane lipids and proteins (Rank, et al., 1985).  Sickle trait red cells normally produce little in the way of such products.  If the infected sickle trait red cells form sickle polymer due to the low oxygen tension produced by parasite metabolism, the cells might generate enough hemin to damage the parasites (Orjih, et al., 1985).

Higher immune response against Malaria in people with sickle cell trait ?
It's the opposite that happen.  Maternal antibodies passed to newborns provide some protection from malaria for the first several months of life.  From then on, the baby's immune system develops.

Epidemiological studies in regions with endemic malaria show that antibody titers to P. falciparum are lower in children with sickle cell trait than in children with genes only for hemoglobin A (Cornille-Brogger, et al., 1979). This, researchers suggested, reflects a lower parasite burden in children with sickle cell trait due to clearance of the infected red cells.  Analysis of people with sickle cell trait and people homozygous for hemoglobin A in the regions with endemic malaria in fact show a lower mean parasite burden in people with sickle cell trait relative to hemoglobin A homozygotes (Fleming, et al., 1979).  In contrast, children with sickle cell disease (not trait) have a high fatality rate, with acute malarial infections being a chief cause of death (Fleming, 1989).

References :
1. Anastasi J. 1984. Hemoglobin S-mediated membrane oxidant injury: protection from malaria and pathology in sickle cell disease. Med Hypotheses 14: 311-320.

2. Cornille-Brogger R, Fleming AF, Kagan I, Matsushima T, Molineaux L. 1979. Abnormal haemoglobins in the Sudan savanna of Nigeria. II. Immunological response to malaria in normals and subjects with sickle cell trait. Ann Trop Med Parasitol 73:173-183

3. Fleming AF, Storey J, Molineaux L, Iroko EAm, Attai ED. 1979. Abnormal haemoglobins in the Sudan savanna of Nigeria. I. Prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival. Ann Trop Med Parasitol 73:161-172.

4. Fleming AF. 1989. The presentation, management and prevention of crisis in sickle cell disease in Africa. Blood Rev 3: 18-28.

5. Martin TW, Weisman IM, Zeballos RJ, Stephenson SR. 1989. Exercise and hypoxia increase sickling in venous blood from an exercising limb in individuals with sickle cell trait. Am J Med 87:48-56.

6. Luzzatto L, Nwachuku-Jarrett ES, Reddy S. 1970. Increased sickling of parasitised erythrocytes as mechanism of resistance against malaria in the sickle-cell trait. Lancet 1(7642):319-321.

7. Orjih AU, Chevli R, Fitch CD. 1985. Toxic heme in sickle cells: an explanation for death of malaria parasites. Am J Trop Med Hyg 34:223-227.

8. Roth Jr, EF, Friedman M, Ueda Y, Tellez I, Trager W Nagel RL. 1978. Sickling rates of human AS red cells infected in vitro with Plasmodium falciparum malaria. Science 202: 650-652.

9. Roth EF Jr, Raventos-Suarez C, Rinaldi A, Nagel RL. 1983. Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum. Proc Natl Acad Sci U S A 80:298-299.

10. Rank BH, Carlsson J, Hebbel RP. 1985. Abnormal redox status of membrane-protein thiols in sickle erythrocytes. J Clin. Invest. 75: 1531-1537.

11. WHO Factsheets

12. Malaria and the Red Cell



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