Mystery of resistance to malaria solved in new study

November 11, 2011 by Lin Edwards, Medical Xpress report
This photomicrograph of a blood smear contains a macro- and microgametocyte of the Plasmodium falciparum parasite. Credit: Wikipedia.

(Medical Xpress) -- Malaria is a disease caused by parasites passed to humans via the bites of infected mosquitoes. Globally, the disease causes over a million deaths every year, and is especially rife in parts of Africa and Asia. The parasites infect red blood corpuscles (the hemoglobin-containing cells that carry oxygen around the body) and hijack the support structure within the cells. Some people are known to be naturally resistant to the serious effects of malaria, and scientists have wondered for decades exactly how their resistance functions. Now new research gone a long way to solving the mystery.

It has been known for decades that some people in Africa and elsewhere who have a mutated gene that causes sickle cell anemia also have to malaria because their red blood corpuscles contain an unusual form of hemoglobin―hemoglobin S, which results in the hemoglobin aggregating within the cell. Possessing only one copy of the mutated hemoglobin S makes the person a largely asymptomatic carrier, while two copies produces symptomatic sickle-cell anemia. In both cases the mutation gives some protection against malaria. Another mutation, hemoglobin C, causes hemolytic when two copies of the mutation are present, and this form also protects against malaria.

In a paper published in Science, researcher Marek Cyrklaff, of Heidelberg University in Germany, and colleagues in Germany and Burkina Faso, report that the unusual forms of hemoglobin in the red prevent the malaria parasite, Plasmodium falciparum, from hijacking the actin filaments that provide the skeleton scaffolding within the cell. They compared healthy and infected red corpuscles containing 'normal' hemoglobin with healthy and infected cells containing hemoglobin S or hemoglobin C. Using powerful cryoelectron tomography, the scientists discovered that in normal healthy cells the filaments of actin protein are short and located beneath the outer cell membrane , where they provide a support structure for the cell and makes it strong but pliable enough to pass through the tiniest blood vessels.

In red blood cells with normal hemoglobin, the malaria parasite Plasmodium falciparum establishes a trafficking system (yellow). The parasite’s proteins - encased in transport envelopes - (turquoise) use this system to directly access the cell surface of the red blood cell. Photo: courtesy of Science/AAAS.

In infected cells with normal hemoglobin they found the actin protein was in long filaments, which the parasite used to build a cytoskeleton, or intracellular bridge, within the cell to transport its own manufactured protein, adhesin, to the surface of the cell. The effect of adhesin, as its name suggests, is to make adjoining cells stick together and to stick the cells to the blood vessel walls, causing the inflammation responses characteristic of malaria. In the hemoglobin S and C cells, the bridge could not be completed and the adhesin could not be effectively transported to the cell surface, thus reducing cell stickiness.

The scientists also found, after further experiments, that hemoglobin C and S are more easily oxidized than the unmutated form, and when actin filaments were placed with the hemoglobin, the C and S forms resulted in shorter actin filaments than normal hemoglobin, as did oxidized .

Malaria is most often treated with quinine, but clinical trials of a vaccine are now being carried out in Africa by GlaxoSmithKline, and the results look promising, with a 65% effectiveness rate. The new research suggests that further drugs could eventually be developed that interfere with the parasite's ability to use the actin filaments for its own purposes.

Explore further: Mystery solved: How sickle hemoglobin protects against malaria

More information: Hemoglobins S and C Interfere with Actin Remodeling in Plasmodium falciparum–Infected Erythrocytes, Science, DOI: 10.1126/science.1213775

ABSTRACT
The hemoglobins S and C protect carriers from severe Plasmodium falciparum malaria. Here, we found that these hemoglobinopathies affected the trafficking system that directs parasite-encoded proteins to the surface of infected erythrocytes. Cryoelectron tomography revealed that the parasite generated a host-derived actin cytoskeleton within the cytoplasm of wild-type red cells that connected the Maurer's clefts with the host cell membrane and to which transport vesicles were attached. The actin cytoskeleton and the Maurer's clefts were aberrant in erythrocytes containing hemoglobin S or C. Hemoglobin oxidation products, enriched in hemoglobin S and C erythrocytes, inhibited actin polymerization in vitro and may account for the protective role in malaria.

Related Stories

Mystery solved: How sickle hemoglobin protects against malaria

April 28, 2011
The latest issue of the journal Cell carries an article that is likely to help solve one of the long-standing mysteries of biomedicine. In a study that challenges currently held views, researchers at the Instituto Gulbenkian ...

Researchers reveal potential treatment for sickle cell disease

November 2, 2011
A University of Michigan Health System laboratory study reveals a key trigger for producing normal red blood cells that could lead to a new treatment for those with sickle cell disease.

Scientists reverse sickle cell anemia by turning on fetal hemoglobin

October 13, 2011
Not long after birth, human babies transition from producing blood containing oxygen-rich fetal hemoglobin to blood bearing the adult hemoglobin protein. For children with sickle cell disease, the transition from the fetal ...

Recommended for you

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Vendicar_Decarian
1 / 5 (1) Nov 12, 2011
Why are government scientists wasting their time with this nonsense.

Curing Malaria is just not profitable and hence is not in the best interest of the taxpayer.

AtomThick
not rated yet Nov 12, 2011
...Curing Malaria is just not profitable and hence is not in the best interest of the taxpayer.


Are you a taxpayer in germany?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.