Cryo-EM Reveals How Malaria Parasites Invade Blood Cells

Results of cryo-electron microscopy (cryo-EM) studies revealed the molecular mechanism by which the Plasmodium vivax malaria parasite binds to and invades red blood cells in the human host.

Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. P. vivax is one of the five species of malaria parasites that commonly infect humans. Although it is less virulent than Plasmodium falciparum, the deadliest of the five human malaria parasites, P. vivax malaria infections can lead to severe disease and death. P. vivax is believed to have originated in Asia and is found mainly in Asia and Latin America – where it accounts for 65% of malaria cases - and in some parts of Africa. However, latest studies have shown that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human P. vivax, findings that indicate that human P. vivax is actually of African origin.

Cryo-EM is an analytical technique that provides near-atomic structural resolution without requirements for crystallization or limits on molecular size and complexity imposed by the other techniques. Cryo-EM allows the observation of specimens that have not been stained or fixed in any way, showing them in their native environment while integrating multiple images to form a three-dimensional model of the sample.

Prior studies indicated that P. vivax used the human transferrin receptor 1 (TfR1) to gain access to red blood cells. TfR1-deficient erythroid cells were refractory to invasion by P. vivax, and anti-PvRBP2b (P. vivax reticulocyte-binding protein 2b) monoclonal antibodies inhibited reticulocyte binding and blocked P. vivax invasion in field isolates.

In a follow-up study, investigators at the Walter and Eliza Hall Institute (Melbourne, Australia) utilized high-resolution cryo-EM to establish the structure of a complex of PvRBP2b bound to human TfR1 and transferrin.

The investigators reported in the June 27, 2018, online edition of the journal Nature that PvRBP2b residues involved in the complex formation were conserved, suggesting that antigens could be designed that would act across P. vivax strains. Functional analyses of TfR1 highlighted how P. vivax hijacked TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron.

"We have now mapped, down to the atomic level, exactly how the parasite interacts with the human transferrin receptor," said Dr. Wai-Hong Tham, a laboratory head in the division of infection and immunity at the Walter and Eliza Hall Institute. "This is critical for taking our original finding to the next stage - developing potential new antimalarial drugs and vaccines. Cryo-EM is really opening doors for researchers to visualize structures that were previously too large and complex to "solve" before."

"It is basically a design challenge. P. vivax parasites are incredibly diverse - which is challenging for vaccine development. We have now identified the molecular machinery that would be the best target for an antimalarial vaccine effective against the widest range of P. vivax parasites," said Dr. Tham. "With this unprecedented level of detail, we can now begin to design new therapies that specifically target and disrupt the parasite's invasion machinery, preventing malaria parasites from hijacking human red blood cells to spread through the blood and, ultimately, be transmitted to others."

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Walter and Eliza Hall Institute