Study finds parasite protein helps Toxoplasma survive crowded cells

A Whitehead Institute-led study published Aug. 11 in Cell identifies TgPRO, a parasite-specific protein that helps Toxoplasma gondii adapt to crowded, oxygen-stressed conditions inside host cells. The finding could help explain how the parasite persists during chronic infection and points to a possible drug target.

Why it matters: - Toxoplasma gondii infects hundreds of millions of people worldwide and can cause severe disease in people with weakened immune systems and developing fetuses. - The parasite can persist for years by forming cysts in tissue, including brain and muscle, which makes infection chronic. - Understanding how Toxoplasma survives crowded cysts could expose weak points for new treatments.

What happened: - Researchers in the lab of Whitehead Institute Member Sebastian Lourido, who is also an associate professor of biology at MIT, identified TgPRO, a parasite-specific protein that helps Toxoplasma manage oxidative stress. - The study was published Aug. 11 in Cell. - Christopher Giuliano, a former graduate student, and Chinmay Kalluraya, a current graduate student in the Lourido lab, led the work as co-first authors. - The team found that TgPRO controls genes involved in energy production and iron use.

The details: - A genome-wide CRISPR screen compared Toxoplasma growth at low and high densities to find genes needed specifically in crowded conditions. - The screen highlighted pathways tied to NAD and NADP, molecules that support energy production and protection from oxidative damage. - TgPRO became a top candidate because it was especially important when parasites were crowded. - Parasites without functional TgPRO accumulated more reactive oxygen molecules and competed poorly at high density. - Loss of TgPRO disrupted the mitochondrion and changed how the parasite processed glucose and other nutrients. - Extra iron, or restoration of a key chemical balance inside the mitochondrion, improved growth in TgPRO-deficient parasites. - TgPRO is an RNA-binding protein that attaches to and stabilizes a select set of messages involved in nutrient use, mitochondrial activity and iron-sulfur cluster assembly. - Iron-sulfur clusters are small structures many enzymes need to function. - Lower oxygen levels reduced oxidative stress and partly restored growth in parasites lacking TgPRO. - The finding matters because Toxoplasma is often grown in labs at atmospheric oxygen levels, which are higher than oxygen levels in most animal tissues. - Mice infected with parasites lacking functional TgPRO developed smaller brain cysts during chronic infection. - TgPRO shows little resemblance to known regulators in mammals, yeast and bacteria, but it controls many of the same kinds of stress-response genes. - The study frames that similarity as convergent evolution: different organisms arrived at different molecular machinery to solve a similar problem. - The work was supported by NIH grants AI144369 and AI158501, the Burroughs Wellcome Fund grant 1021330, a Wellcome Trust Early Career Award, a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society, and donor-advised funding through CARIGEST SA.

Between the lines: - The study identifies the first dedicated regulator of metabolic gene expression found in apicomplexans, the parasite group that includes Toxoplasma and malaria-causing organisms. - That makes TgPRO a potential therapeutic angle because blocking pathways it controls could make Toxoplasma more vulnerable to antiparasitic drugs that trigger oxidative stress, though that approach still needs testing. - The results also suggest oxygen conditions can strongly shape parasite metabolism, which may affect how researchers study Toxoplasma in the lab. - The chronic-stage cyst remains hard to study, so the smaller brain cysts provide an important clue about how the parasite persists for months or years.

What's next: - Researchers will need to test whether inhibiting TgPRO-controlled pathways can improve the effect of antiparasitic drugs. - The findings should also push more work on how oxygen levels and nutrient stress shape parasite metabolism in chronic infection. - The study adds a new framework for examining how apicomplexan parasites regulate metabolism inside hosts.

The bottom line: - Toxoplasma appears to rely on a previously unknown RNA-binding protein to survive the crowded, stressful environment of chronic infection, and that weakness may be useful for future therapies.