Scientists have identified a parasite-specific protein named TgPRO that helps Toxoplasma gondii manage oxidative stress and survive chronic infections in crowded conditions, according to a study published on August 11 in the journal Cell.
How Toxoplasma Survives Crowded Tissue Cysts
Toxoplasma gondii infects hundreds of millions of people worldwide. While infections are frequently mild, the parasite can cause severe illness in developing fetuses and individuals with compromised immune systems. The organism persists for years by forming long-lived cysts in host tissues, establishing a chronic infection. Inside a single brain or muscle cell tissue cyst, hundreds of parasites can pack tightly together. According to researchers, this crowded state creates severe physiological strain, making nutrients scarce, waste accumulate, and energy-producing reactions potentially damaging.
To determine how the parasite adapts to these harsh conditions, researchers in the lab of Whitehead Institute Member and Massachusetts Institute of Technology Associate Professor of Biology Sebastian Lourido utilized a genome-wide CRISPR screen. According to the study, led by co-first authors Christopher Giuliano, a former graduate student, and Chinmay Kalluraya, a current graduate student, the screen compared parasites growing at low and high densities to identify essential genes. The screen highlighted metabolic pathways that produce or recycle NAD and NADP—molecules vital for energy production and defense against oxidative damage—and pointed directly to TgPRO, a previously unstudied protein essential for parasite survival during crowding.
The Molecular Mechanism of TgPRO
Experiments revealed that parasites lacking functional TgPRO accumulated higher levels of reactive oxygen molecules and struggled to compete when populations were dense. According to the research team, losing TgPRO disrupted the mitochondrion—the cellular structure responsible for supplying energy—and altered how the parasites processed glucose and other nutrients. Restoring chemical balances or supplying additional iron inside the mitochondrion improved parasite growth, directly linking TgPRO’s function to iron-dependent energy metabolism.
Further investigation established that TgPRO functions as an RNA-binding protein. The protein attaches to specific ribonucleic acid messages used by cells to build proteins. Researchers found that TgPRO binds and stabilizes a targeted set of messages involved in nutrient utilization, mitochondrial function, and the assembly of iron-sulfur clusters required by numerous enzymes.
Potential Therapeutic Implications
The discovery uncovers the first dedicated regulator of metabolic gene expression identified in apicomplexans, a group of parasites that includes both Toxoplasma and the organisms responsible for malaria. According to the study authors, these findings point toward a potential therapeutic strategy. Inhibiting the pathways regulated by TgPRO could render Toxoplasma more vulnerable to antiparasitic medications that induce oxidative stress, though this approach still requires experimental testing.
