Plasmodium parasite infecting

a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

New research indicates that manipulating the permeability of parasitophorous vacuoles could defeat malaria parasites.

The researchers unearthed this finding while studying the way in which the Toxoplasma gondii parasite, which causes toxoplasmosis, and Plasmodium parasites,

which cause malaria, access vital nutrients from their host cells.

The team described this work in Cell Host & Microbe.

Roughly a third of the world’s deadly infectious diseases are caused by pathogens that spend a large portion of their life inside parasitophorous vacuoles. This type of vacuole separates the host cytoplasm and the parasite by a membrane, protecting the parasite from the host cell’s defenses and providing an environment tailored to the parasite’s needs.

However, the membrane of the vacuole also acts as a barrier between the parasite and the host cell. This makes it more difficult for the parasite to release proteins involved in the transformation of the host cell beyond the membrane to spread the disease and for the pathogen to gain access to vital nutrients.

“Ultimately, what defines a parasite is that they require certain key nutrients from their host,” said study author Dan Gold, PhD, of the Massachusetts Institute of Technology in Cambridge.

“So they have had to evolve ways to get around their own barriers to gain access to these nutrients.”

Previous research suggested the vacuoles are selectively permeable to small molecules, allowing certain nutrients to pass through pores in the membrane. But until now, no one has been able to determine the molecular makeup of these pores or how they are formed.

When studying Toxoplasma, Dr Gold and his colleagues discovered 2 proteins secreted by the parasite, known as GRA17 and GRA23, which are responsible for forming these pores in the vacuole. The researchers discovered the proteins’ roles by accident while investigating how the parasites are able to release their own proteins out into the host cell beyond the vacuole membrane.

Similar research into how the related Plasmodium pathogens perform this trick revealed a protein export complex that transports encoded proteins from a parasite into its host red blood cell, which transforms the cell in a way that is vital to the spread of malaria.

“The clinical symptoms of malaria are dependent on this process and this remodeling of the red blood cell that occurs,” Dr Gold said.

The researchers identified proteins secreted by Toxoplasma that appeared to be homologues of this protein export complex in Plasmodium. But when they stopped these proteins from functioning, the team found it made no difference to the export of proteins from the parasite beyond the vacuole.

“We were left wondering what GRA17 and GRA23 actually do if they are not involved in protein export, and so we went back to look at this longstanding phenomenon of nutrient transport,” Dr Gold said.

When they added dyes to the host cell and knocked out the 2 proteins, the researchers found that it prevented the dyes flowing into the vacuole.

“That was our first indication that these proteins actually have a role in small-molecule transfer,” Dr Gold said.

When the researchers expressed a Plasmodium export complex gene in the modified Toxoplasma, they found the dyes were able to flow into the vacuole once again, suggesting this small-molecule transport function had been restored.

Since these proteins are only found in the parasite phylum Apicomplexa, to which both Toxoplasma and Plasmodium belong, they could be used as a drug target against the diseases they cause, the researchers said.

“This very strongly suggests that you could find small-molecule drugs to target these pores, which would be very damaging to these parasites but likely wouldn’t have any interaction with any human molecules,” Dr Gold said. “So I think this is a really strong potential drug target for restricting the access of these parasites to a set of nutrients.”

Team discovers target for antimalarial drugs