red between parasites that used sialic acid and those that did not. The first of these was a gene known as P. falciparum reticulocyte-binding like homolog 4 (PfRh4) that's similar to other genes known to play a role in the invasion of red blood cells by P. falciparum and related parasites. The second gene, EBA165, did not appear to produce a functional protein, and the scientists suspect it had been activated only because it was physically adjacent to PfRh4. Using a second, more quantitative approach, the team found that the two genes were 60- to-80 times more active in the sialic acid-independent parasites than in those that needed the sugar for cell entry.
These results suggested that activation of the PfRh4 gene was required for the parasite to make the switch to sialic acid-independent invasion. Indeed, the team was able to find PfRh4 protein in sialic acid-independent parasites, but not in the sialic acid-dependent lines. And when the group constructed parasites in which the PfRh4 gene was disrupted, they found that those parasites would not grow in the absence of sialic acid, although they grew normally on cells with the sugar further suggesting that activation of the PfRh4 gene is required for switching from sialic acid-dependent to independent invasion.
"Activation of PfRh4 represents a previously unknown mechanism to switch invasion pathways and provides P. falciparum with exquisite adaptability in the face of receptor changes and immune system responses," the team concluded.
The results have important implications for the design of anti-malaria vaccines. The molecule on the parasite that binds to sialic acid receptors on host cells is considered a target in anti-malaria medications, but Cowman notes that if only that gene is blocked, some parasites can still use PfRh4 to switch to other means of entry. "If both genes are disrupted, it blocks both ways of getting in," he says.
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Contact: Brad Allen
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