Sickle cell disease is an inherited disease that is passed from parents to their offspring. It is caused by a single amino acid mutation (substitution of valine for glutamic acid at 6th position) of beta hemoglobin chain. Individual with sickle cell disease received two copies of abnormal gene from both parents while individual (heterozygous) that are carriers for sickle cell received one normal and one abnormal gene from their parents.
Researchers at the Institution Gubenkien de Ciencia (IGC) in Portugal , have proved the molecular mechanism of how sickle cell hemoglobin provide survival advantage against malaria caused by plasmodium falciparum. The study shows that a mice that was genetically engineered to produced one copy of sickle hemoglobin similar to sickle cell trait did not produce cerebral malaria which means that individual with sickle cell trait are protected against severe malaria.
Another study by molecular biologist at Heidelberg university in Germany explained more about why carries (sickle cell traits) are protected against malaria. Normally, when malaria parasite invade red blood cell , it will replicate. The infected red blood cell will be removed by an organ called spleen. The case of individual with sickle cell trait is different. when infected, the parasite inside the red blood cell moves a molecules called adhesion to the cell surface to make red blood cell adhere to blood capillaries causing it to be sticky , preventing the infected cells from being removed by the spleen.
There is another protein called actin . it is found in one of the skeletal element in every cell . So, when these parasite invade red blood cell, it hijack the actin cytoskeleton and use it to build a cable system out of actin filament to carry the adhesion to cell surfaces . sickle cells from carriers with malaria parasite was observes through electron microscope and it shows that their actin filament are shorter than normal. Actin filament is usually long in normal infected red blood cells. The short actin in the sickle cell shows that it is not fully develop. In sickle cells for some reason , the parasite are not able to form the functional actin filament network in host cells.
The picture above shows sickle cells infected with Plasmodium falciparum (green) collapse and prevent the parasite from interfering with the cell’s actin proteins, protecting the host against malaria .
I selected this topic because I was born in a country where malaria is endemic. I observed people who had malaria suffer greatly while some recovered quickly. sickle cell trait is common in my country too. So, it is really good to know the mystery and solve the puzzle behind malaria parasite and sickle cells.
Below is a graph that a CDC birth cohort studies conducted in collaboration with Kenya medical research institutes.
Graph of survival curves (“survival function estimates”) of children without any sickle cell genes (HbAA), children with sickle cell trait (HbAS), and children with sickle cell disease (HbSS). Those who had the sickle cell trait (HbAS) had a slight survival advantage over those without any sickle cell genes (HbAA), with children with sickle cell disease (HbSS) faring the worst.
EDITH
Citation
Instituto Gulbenkian de Ciencia. (2011, April 29). Mystery solved: How sickle hemoglobin protects against malaria. ScienceDaily. Retrieved October 12, 2017 from http://www.sciencedaily.com/releases/2011/04/110428123931.htm
Instituto Gulbenkian de Ciencia. “Mystery solved: How sickle hemoglobin protects against malaria.” ScienceDaily. http://www.sciencedaily.com/releases/2011/04/110428123931.htm (accessed October 12, 2017).
Reference: Protective Effects of the Sickle Cell Gene Against Malaria Morbidity and Mortality. Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V. Lancet 2002; 359:1311-1312
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I think it is very interesting to learn more about the heterozygous advantage present in sickle cell anemia. The article discusses how individuals in malaria prone regions (many countries in Africa) can benefit from being a carrier (heterozygous) for the sickle cell trait. Those that are homozygous dominant don’t have the trait and will not exhibit sickle anemia symptoms but are open for mosquitoes to transfer malaria. On the other hand, individuals that are homozygous recessive and have 2 alleles for sickle cell anemia will most likely exhibit severe cases of sickle cell anemia and also the effects of malaria. Through evolution, the heterozygous individual has adapted to the environment and increased their survival chances against malaria by using the abnormal red blood cell allele. I learned how the protein, actin is used in the parasite-host relationship as a method of transferring adhesion in order for the infected cells to stick to capillary surfaces and avoid being filtered by the spleen. The study indicated that carriers of sickle cell depicted short actin filaments (when viewed under microscopy) indicating an invader (such as the malaria parasite) cannot fully transfer its material in the host cells. This adaptation in the heterozygotes allows the individuals to be protected against malaria and potentially other diseases. I wonder if there have been other studies conducted, identifying sick cell carriers being protected from other diseases prone to the same region. Why is malaria the only disease the heterozygotes have advantage over?
I had found an article discussing the microbes in a mosquito’s gut potentially helping fight against malaria. It would be useful to manipulate the microbes from the vector (female Anopheles) that carries the disease (Plasmodium falciparum) and use it to protect against malaria. Even though there are several insecticides produced to try and combat the spread of malaria, nothing seems to be working effectively. Researchers have discovered a bacterium in the genus Serratia, which is capable of spreading through the female Anopheles body and even into the larvae of the next generation. Scientists are hoping to manipulate this bacterium with Plasmodium- resistant genes that can be transferred from one mosquito to another to battle malaria. Another team is studying genes that increase the production of Rel2 (a protein involved in blocking gut infections). The gene gives mosquitoes a competitive advantage in mating and passing on its genes. The anti-Plasmodium gene is being introduced with genetic modification into the genes producing Rel2 in the hopes the passing on of anti-malaria genes will increase the likelihood of the next generation being resistant to malaria. All research is being combined to increase the chances of stopping the spread of malaria. There is hope when reading these articles, that in the near future malaria will not be as prevalent around the globe.
Chanel Athulathmudali
Article Source: Servick, K. (2017, September 28). The microbes in a mosquito’s gut may help fight malaria. Science Magazine. Retrieved October 14, 2017 from http://www.sciencemag.org/news/2017/09/microbes-mosquito-s-gut-may-help-fight-malaria.
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