Malaria parasites become “TRAPped” without an I domain

Plasmodium parasites need a specific part of a protein called TRAP to move around and infect their hosts, but a substitute from a distant relative can do the job too.
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Sporozoites of a rodent-infecting malaria parasite gliding under a microscope. The parasites have been engineered to produce a fluorescently labeled version of the TRAP surface protein. Image credit: Klug et al. (CC BY 4.0)

Malaria is an infectious disease caused by single-celled parasites known as Plasmodium. Humans and other animals with backbones – such as birds, reptiles and rodents – can become hosts for these parasites if an infected female mosquito feeds on their blood. Likewise, healthy mosquitoes can in turn become infected with Plasmodium if they feed on the blood of an infected animal.

To complete their life cycle, Plasmodium parasites within a mosquito must become spore-like cells called sporozoites. These sporozoites are highly mobile and can get into the mosquitoes’ salivary glands, meaning they can be passed on to a new host when the insect feeds. During a mosquito bite the sporozoites are spat into the skin of the potential host, where they then need to migrate rapidly to enter the bloodstream. Once in the blood, the sporozoites can then get into liver cells and begin a new infection. One protein called TRAP, which is found on the surface of the sporozoites, is important for their migration and the infection of the salivary glands or liver. Yet it was not known how this happens at the level of the individual proteins involved.

Klug et al. have now tested how a part of the TRAP protein, called the I domain, contributes to the infection process. In the experiments, the I domain of TRAP was deleted which showed that the sporozoites need this domain to be able to move around and get into the host tissues. Without the I domain the sporozoites were stuck and could not successfully infect either the mosquitoes, the livers of mice, or human liver cells grown in the laboratory. Klug et al. then replaced the Plasmodium I domain of TRAP with the I domain from a distantly related parasite called Toxoplasma gondii, which causes a condition known as toxoplasmosis. The I domain from Toxoplasma allowed the Plasmodium parasites to infect the host tissues again. This observation was unexpected because Toxoplasma and Plasmodium parasites have evolved separately over the last 800 million years and Toxoplasma does not infect insects.

These findings suggest that the I domain of TRAP evolved to bind several other proteins in different tissues and hosts. Future studies will investigate which other parasite proteins TRAP works with to guide sporozoites to the salivary glands or liver. Knowledge of how these proteins act together may lead to new approaches for treating or preventing malaria. For example, some treatments could stop sporozoites from entering liver cells.