Key Protein Helps Toxoplasma Parasite Thrive in a Crowd

Containing the spread of the parasite Toxoplasma gondii is like trying to catch juice in a sieve. The organism, just a few micrometers in size, has infected more than two billion people worldwide.¹ That includes roughly 60 million people in the United States. Luckily, those with a healthy immune system can keep the parasite at bay.

But people with weakened immune systems are vulnerable to infection and at risk of headaches and seizures, so studying how it has become so successful is an important topic for researchers. In long-term infections, T. gondii creates cysts throughout the body, in which hundreds of parasites live crammed together side by side. In a new study published in Cell, researchers have shown how the parasites thrive in these cramped conditions, where nutrients are scarce and waste quickly builds up.² The findings also point to a possible therapy for T. gondii that could make antiparasitic drugs more effective.

Genome Screen Identifies Parasite’s Secret Strategy

The scientists behind the new study screened T. gondii’s genome in two different conditions: when the parasite was growing at low density and when it was packed near other parasites. This approach was designed to find genes that increased expression when the parasite entered crowded conditions. “A genome-wide screen was a powerful way to ask how crowding affects parasite fitness,” said Chinmay Kalluraya, a biologist at the Massachusetts Institute of Technology (MIT) and coauthor of the new study, in a statement.

This search highlighted one previously unidentified protein, which the team called T. gondii parasite response to oxidation (TgPRO). This protein is a regulator of several key components of the parasite’s metabolism. “TgPRO emerged as very important at high density. Because almost nothing was known about it, we wanted to understand what it was doing,” said Kalluraya.

The team found that T. gondii was put under a significant metabolic strain in crowded conditions. This burden included oxidative stress, where levels of unstable reactive oxygen species build up. These species can damage cells, so keeping them suppressed is important. The team found that TgPRO balanced oxidation in the parasite. When the team switched TgPRO off in the parasites’ genomes, their reactive oxygen species levels increased, which affected their survival under high-density conditions.

Clues to Developing Toxoplasma Therapies

Turning TgPRO off changed other components of the parasites’ metabolisms. Mutants lacking the protein processed iron and glucose differently and had changes to activity levels in their energy-producing mitochondria. The scientists showed that TgPRO suppression caused all these changes because normally, the protein binds to nearly 90 RNA transcripts involved in key metabolic functions before they are translated into proteins.

The team then wanted to see how TgPRO contributed to long-term toxoplasmosis infections. They showed that mice infected with mutant T. gondii parasites had smaller cysts in their brains when TgPRO was suppressed. The researchers hypothesized that the parasite likely relies on TgPRO to switch into a different metabolic mode when it hunkers down into cysts. “Showing that TgPRO affects cyst growth suggests that these same metabolic changes are needed in the brain and gives us clues about how the parasites persist there for months or years,” said biologist Christopher Giuliano, who contributed to the project while at MIT, in the statement.