How Blood Cells Thwart Malaria

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.