Menu

How Blood Cells Thwart Malaria

The sickle cell anemia mutation may protect against malaria by preventing the parasite from sending dangerous proteins to the red blood cell surface.

Nov 10, 2011
Tia Ghose

Sickle cells infected with malaria stained with green flourescent proteinSCIENCE/AAAS

Two hemoglobin mutations, including one that causes sickle cell anemia, may protect people from severe malaria by gumming up the cellular machinery the parasite uses to transmit deadly proteins to the cell surface. The findings, published today (November 10) in Science Express, suggest potential ways to fight the deadly disease.

“It’s a great study,” said Rick Fairhurst, who studies malaria pathogenesis and immunity at the National Institute of Allergy and Infectious Diseases, and was not involved in the study. “It really takes us a huge, giant leap forward.” By showing what mutations enable cells to avoid the deadliest consequences of malaria, the research may also point to potential treatment targets, he added.

For decades, researchers have known that people who carry a gene for sickle cell anemia are highly resistant to dying from malaria. Research has shown that it is the mutation to one of their hemoglobin genes, which codes for the oxygen-transporting protein in red blood cells, that was responsible for the fortuitous effect, and that other mutations in that same gene were also protective. But despite years of research, no one knew why.

Fairhurst and his colleagues published a paper showing that compared to normal cells, red blood cells carrying two hemoglobin mutations had lower surface concentrations of a virulent, sticky protein produced by the malaria parasite, Plasmodium falciparum. The protein, which is normally shuttled from the parasite’s protein making factory inside the cells to the cell surface, prevents the body from clearing infected blood cells. But in the blood cells with mutated hemoglobin, that didn’t seem to happen—the parasite proteins never made it to the surface of the cells.

To find out why, parasitologist Michael Lanzer of Heidelberg University in Germany and his colleagues flash froze red blood cells with and without the mutations and used electron microscopy to visualize the cells before and after infection.

They found that uninfected cells contained short pieces of actin that help keep the membrane skeleton rigid. After infection, in normal cells, long actin filaments appeared, linking a cellular component made by the parasite called the Maurer’s cleft, which looks a bit like a stack of pancakes, to the cell membrane. “We concluded that the parasite mines that actin from the membrane skeleton of the host, and uses this mined actin to generate actin filaments of its own design,” Lanzer said—namely to transmit the proteins to the outside surface of the red blood cell.

By contrast, in cells with mutated hemoglobin, the Maurer’s cleft looked more like a big blob and the disordered actin filaments did not connect the cleft to the cell membrane. Somehow, it seemed, the mutations were preventing the parasite from setting up its protein factory effectively, thereby reducing protein transport outside the cell.

The team also took a closer look at the hemoglobin, and found that  the difference between the mutated and wild-type cells was that mutated forms were more easily oxidized.  When they placed actin filaments in the presence of both the normal and mutated copies of hemoglobin, the researchers found that mutated forms of hemoglobin led to shorter actin chains than wild-type hemoglobin. Actin placed with oxidized hemoglobin similarly failed to form long chains, suggesting that oxidation was indeed responsible for the difference in the parasite’s protein machinery seen in cells with mutated and normal hemoglobin.

Taken together, the findings suggest that the hemoglobin mutations blunt the deadliness of malaria because the oxidized hemoglobin inhibits actin reorganization, thereby preventing the malaria parasite from shuttling its proteins to the surface red blood cells, Lanzer said.

Future work should confirm that the same effects are seen in cells that carry only one copy of the mutated hemoglobin, since the vast majority of people who carry these mutations and have a survival advantage against malaria are heterozygous for the mutated hemoglobin, Fairhurst said.

Understanding how the body gets around malaria’s deadliness could guide the design of drug therapies, he added, for instance by finding small molecules that inhibit the parasite’s protein trafficking machinery.

“Mother Nature had 10,000 years or so to mutate the genome in ways that would actually protect against death,” Fairhurst said. “We want to use these mutations to teach us something about how you protect children.”

M. Cyrklaff, et. al, “"Hemoglobins S and C interfere with Actin Remodeling in Plasmodium falciparum-Infected Erythrocytes," Science Express, doi:10.1126/science.1213775, 2011.

November 2018

Intelligent Science

Wrapping our heads around human smarts

Marketplace

Sponsored Product Updates

Complete Pathology Solutions: Make Every Minute Count

Complete Pathology Solutions: Make Every Minute Count

From sample collection and handling, to fixation and processing, tissue staining, and covering all your IHC and water purification needs—you can have confidence in the quality of your results with MilliporeSigma's one-stop pathology solution.

Preparing Cell Or Tissue Lysates For ELISA Kits

Preparing Cell Or Tissue Lysates For ELISA Kits

RayBiotech manufactures over 2,000 high fully validated, GMP-compliant ELISA kits. In this blog post we explain how to prepare cell or tissue lysates for ELISA Kits.

Norgen Biotek Achieves Illumina Propel Certification as a Service Provider for Next Generation Sequencing

Norgen Biotek Achieves Illumina Propel Certification as a Service Provider for Next Generation Sequencing

Norgen Biotek Corp., an innovative privately held Canadian biotechnology company focusing primarily on nucleic acid and protein stabilization and purification, as well as providing high quality services to the scientific community, today announced that it has become Propel-Certified through Illumina as a Next Generation Sequencing (NGS) service provider.

Slice® Safety Cutters for Lab Work

Slice® Safety Cutters for Lab Work

Slice cutting tools—which feature our patent-pending safety blades—meet many lab-specific requirements. Our scalpels and craft knives are well suited for delicate work, and our utility knives are good for general use.