Scientists have taken a significant step toward developing a new vaccine for malaria, revealing for the first time an 'atomic-scale' blueprint of how the parasite invades human cells.
Using the Nobel Prize-winning technology cryo-EM (cryo-electron microscopy), the researchers mapped the previously hidden first contact between Plasmodium vivax malaria parasites and young red blood cells they invade to begin the parasites' spread throughout the body. The discovery was published in Nature.
Earlier this year, the team discovered P. vivax parasites use the human transferrin receptor to gain access to red blood cells, a study they published in Science. Now, with the aid of revolutionary cryo-EM technology, the team was able to overcome previous technical challenges to visualise the interaction at an atomic level.
"We've now mapped, down to the atomic level, exactly how the parasite interacts with the human transferrin receptor," one of the author’s said.
P. vivax is the most widespread malaria parasite worldwide, and the predominant cause of malaria in the vast majority of countries outside Africa. Because of its propensity to 'hide' undetected by the immune system in a person's liver, it is also the number one parasite responsible for recurrent malaria infections.
Guided by the 3D map, the team was able to tease out the precise details of the parasite-host interaction, identifying its most vulnerable spots.
"It's 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," author said.
Successful entry of the parasite depends on specific interactions between the P. vivaxreticulocyte-binding protein 2b (PvRBP2b) and transferrin receptor 1 (TfR1).Authors report high-resolution cryo-electron microscopy structure of a ternary complex of PvRBP2b bound to human TfR1 and transferrin, at 3.7 Å resolution.
Mutational analyses show that PvRBP2b residues involved in complex formation are conserved; this suggests that antigens could be designed that act across P. vivax strains. Functional analyses of TfR1 highlight how P. vivax hijacks TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of PvRBP2b in complex with antibody fragments characterize the inhibitory epitopes.
https://www.wehi.edu.au/news/first-malaria-human-contact-mapped-nobel-prize-winning-technology
https://www.nature.com/articles/s41586-018-0249-1
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