How sickle cell gene protects against malaria

The routes: People who develop sickle cell disease have inherited from both parents defective versions of a gene for haemoglobin. Photo: Ritu Raj Konwar  

A team of U.S. scientists has identified a new and surprising way in which those with the gene that causes sickle cell disease are protected from the ravages of malaria.

People who develop sickle cell disease have inherited from both parents defective versions of a gene for haemoglobin, the iron-containing protein in red blood cells that transports oxygen from the lungs to tissues in the body.

Their red blood cells, instead of being disc-like, turn crescent shaped. Such individuals can suffer from anaemia, episodes of pain, serious infections and even organ damage.

Those with the defective gene from only one parent usually escape such health problems.

However, these individuals too get milder forms of malaria rather than the life-threatening kind that can afflict people with the normal gene. This survival advantage has resulted in the faulty gene occurring at higher frequencies in malaria-endemic parts of the world.

Complex life cycle

At one stage during their complicated life cycle, the single-celled Plasmodium parasites, which cause malaria, invade red blood cells and proliferate there, feeding on haemoglobin. In a paper published recently in the journal Cell Host & Microbe, Jen-Tsan Chi and his colleagues at the Duke University Medical Centre in the U.S. noted that short strips of the genetic material RNA, known as microRNA (miRNA), were found at enhanced levels in the red blood cells of people with the sickle cell gene.

Like genes (which are needed to produce proteins), the genetic information to make miRNA too is carried in the DNA of organisms. The miRNA work with other components of a cell to limit the amounts of certain proteins that are churned out.

“Why any miRNAs are present in mature erythrocytes [red blood cells] is a mystery, since there is no ongoing protein synthesis,” observed Manoj Duraisingh of the Harvard School of Public Health and Harvey Lodish of the Whitehead Institute for Biomedical Research in a commentary on Dr. Chi's paper that was published in the same journal.

Dr. Chi and his fellow scientists found that some kinds of miRNA from the red blood cells were getting into Plasmodium falciparum, the parasite that causes the most dangerous forms of malaria. Doing so meant that these miRNA were getting past two membranes, one that surrounds the parasite (known as a parasitophorous vacuolar membrane) as well as the parasite's own cellular covering.

The paper's findings were “intriguing,” according to Pushkar Sharma of the National Institute of Immunology in Delhi who works on the parasite. Only a few of the various miRNA present in the red blood cells were getting in and these were present in the parasite at higher levels than in the red blood cells. The molecular mechanisms that transported those miRNA into the parasite were not clear.

Nor was it clear how a mutation in a gene required for haemoglobin set off increased production of the miRNA, he added.

The Plasmodium parasites are not known to have the molecular machinery that miRNA typically uses to interfere with protein production.

Instead, once inside, the human miRNA got attached to one end of some of the parasite’s messenger RNA (mRNA), which shuttle genetic information from genes to the protein-making apparatus known as ribosomes.

Dr. Chi’s team found that this fusion impaired the loading of mRNA into ribosomes, thereby significantly reducing synthesis of some key proteins of the parasite.

The findings that had been published were “quite staggering” and opened up new avenues for research, remarked Dr. Sharma.

The resistance of sickle cell patients to malaria has been interpreted to involve multiple mechanisms, noted G. Padmanabhan, former director of the Indian Institute of Science at Bangalore, who has studied the malaria parasites for many years. Dr. Chi and his colleagues had uncovered what “appears to be one more mechanism by the host to contain parasite growth.”

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Printable version | Feb 19, 2021 3:22:12 PM |

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