Study unveils how Toxoplasma gondii parasites escape drug treatment

A study by Indiana University School of Medicine researchers sheds new light on how Toxoplasma gondii parasites make the proteins they need to enter a dormant stage that allows them to escape drug treatment. It was recently published with special distinction in the Journal of Biological Chemistry.

Toxoplasma gondii is a single-celled parasite that people catch from cat feces, unwashed produce or undercooked meat. The parasite has infected up to one-third of the world’s population, and after causing mild illness, it persists by entering a dormant phase housed in cysts throughout the body, including the brain.

Toxoplasma cysts have been linked to behavior changes and neurological disorders like schizophrenia. They can also reactivate when the immune system is weakened, causing life-threatening organ damage. While drugs are available to put toxoplasmosis into remission, there is no way to clear the infection. A better understanding of how the parasite develops into cysts would help scientists find a cure.

Through years of collaborative work, IU School of Medicine Showalter Professors Bill Sullivan, PhD, and Ronald C. Wek, PhD, have shown that Toxoplasma forms cysts by altering which proteins are made. Proteins govern the fate of cells and are encoded by mRNAs.

“But mRNAs can be present in cells without being made into protein,” Sullivan said. “We’ve shown that Toxoplasma switches which mRNAs are made into protein when converting into cysts.”

Lead Author Vishakha Dey, PhD, a postdoctoral fellow at the IU School of Medicine and a member of the Sullivan lab, examined the so-called leader sequences of genes named BFD1 and BFD2, both of which are necessary for Toxoplasma to form cysts.

mRNAs not only encode for protein, but they begin with a leader sequence that contains information on when that mRNA should be made into protein.”

Vishakha Dey, PhD, Lead Author

All mRNAs have a structure called a cap at the beginning of their leader sequence. Ribosomes, which convert mRNA into protein, bind to the cap and scan the leader until it finds the right code to begin making the protein.

“What we found was that, during cyst formation, BFD2 is made into protein after ribosomes bind the cap and scan the leader, as expected,” Dey said. “But BFD1 does not follow that convention. Its production does not rely on the mRNA cap like most other mRNAs.”

The team further showed that BFD1 is made into protein only after BFD2 binds specific sites in the BFD1 mRNA leader sequence.

Sullivan said this is a phenomenon called cap-independent translation, which is more commonly seen in viruses.

“Finding it in a microbe that has cellular anatomy like our own was surprising,” Sullivan said. “It speaks to how old this system of protein production is in cellular evolution. We’re also excited because the players involved do not exist in human cells, which makes them good potential drug targets.”

The Journal of Biological Chemistry featured the new study as an “Editor’s Pick” paper, which represent a select group of the journal’s publications judged to be of exceptionally high quality and broad general interest to their readership.

“This paper describes a mechanism by which a parasite that causes toxoplasmosis in humans can respond to stress and allow the parasite to thrive,” said George N. DeMartino, PhD, associate editor of the Journal of Biological Chemistry and a professor at the University of Texas Southwestern Medical Center. “The discovery of this mechanism provides a basis for treating these infections. Moreover, a similar mechanism is important in cancer, suggesting that it may be a therapeutic target for multiple human diseases.”

Additional co-authors on the study include IU School of Medicine’s Michael Holmes, PhD, and Matheus S. Bastos, PhD. The work was funded by the National Institutes of Health and the Showalter Foundation.