L. David Sibley, the Alan A. and Edith L. Wolff Distinguished Professor of Molecular Microbiology at Washington University School of Medicine in St. Louis, has spent decades unraveling the secrets of Toxoplasma gondii, a parasite spread by cats and contaminated water and food. People infected with Toxoplasma can generally control the infection, but the parasite remains in their bodies for life and can reactivate to cause toxoplasmosis, a disease characterized by vision problems and life-threatening complications in the brain.
Sibley’s discoveries have put him at the forefront of the field of parasite biology. A few years ago, he was busy fielding interview requests from journalists about his latest high-profile paper when he opened an email from a woman in Heidelberg, Germany.
“I would like to ask you,” wrote the woman, after explaining that her husband was dying of toxoplasmosis, “how far (near?) is the possibility of human therapy based on your work?”
To Sibley, the email was a wake-up call.
“We always say that we do basic science so that one day there might be an improvement in human health, but we don’t always push hard enough to convert our discoveries into benefits for patients,” Sibley said. “After thinking hard about this issue, my colleagues and I came up with the idea of trying to find chemical compounds that eliminate the chronic stages of the parasite, rather than just control it, like current drug therapies do. We know a lot about the biology of this parasite. My lab has spent 30 years figuring out all the tricks the parasite uses to block the immune system. We have developed sophisticated genetic tools and animal models to monitor infection. All this has led to a pile of high-profile papers, and recognition, but has not really had an impact on people who suffer from this infection. I thought, ‘Why not see if we can identify small molecules that might lead to a curative drug?’”
That plaintive email eventually led Sibley and colleagues – at the California Institute for Biomedical Research (Calibr) in La Jolla, Calif.; the Broad Institute in Cambridge, Mass.; and the International Centre for Genetic Engineering and Biotechnology in New Delhi, India – to launch an effort to identify chemical compounds that eliminate the chronic stages of Toxoplasma and have the potential to be developed into drugs to eradicate the infection. As principal investigator, Sibley has received a $5.5 million grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) to support the research.
Toxoplasma is a parasite that naturally cycles between mice and cats. An infected cat excretes millions of the parasite in its feces in a form known as oocysts, contaminating the soil and water. A mouse gets infected by eating food such as fruit or seeds contaminated with oocysts, and a cat eats the mouse, completing the cycle.
Humans and other animals are accidental participants in this process. Herbivorous animals like cows and sheep can become infected as they graze. People become infected by eating undercooked meat from such animals or unwashed vegetables, or by drinking contaminated water. Some people become infected by failing to wash their hands after cleaning cats’ litter boxes. Once inside a person’s digestive tract, the parasite emerges from the cyst, burrows through the intestinal wall and spreads to the muscle, heart, brain and eyes. There, it develops into a cyst form and remains for the rest of the person’s life.
About a quarter of the world’s population is thought to be infected with Toxoplasma. Most people do not have symptoms because a healthy immune system keeps the parasite in check. In people with compromised immune systems, though, the parasites do not stay in their cysts and instead begin to multiply, causing debilitating, sometimes fatal, damage to the brain, eyes and other organs. Women who become infected during pregnancy may pass the infection to their fetuses, resulting in severe birth defects.
Drugs for toxoplasmosis only target the parasite in the active phase, leaving cysts untouched. Since parasites may emerge from the cysts at unpredictable times, people must continue taking the drugs for prolonged periods, sometimes more than a year. Even so, the risk of relapse is high. Supplementing current therapies with a drug that eliminates the cysts not only would speed up treatment, it would cure the infection.
“Nobody’s ever really looked for drugs that target the latent, cyst phase,” Sibley said. “You can’t just take drugs that work against other microbial infections and repurpose them. That’s been tried and it doesn’t work very well. It’s hard to kill the cyst form. That’s why they form cysts: to protect themselves when they are in an inhospitable environment. We’re going to have to really dig into the biology and that’s difficult and takes time. Since the potential monetary payoff will likely be small, big pharma just isn’t interested. If potential drugs are going to be found, they will have to be started by academic labs.”
The research project is already underway. A group led by Stuart Schreiber, a chemical biologist at the Broad Institute, screened some 80,000 small molecules for their ability to inhibit parasite growth and identified several promising leads. A group of structural biologists at the International Centre for Genetic Engineering and Biotechnology led by Amit Sharma is analyzing how the initial leads interact with their target enzyme. A detailed understanding of the molecular structure will inform efforts to optimize the compounds. Medicinal chemist Arnab Kumar Chatterjee leads a group at Calibr that is creating new molecules based on the promising leads but with improved potency, safety, bioavailability and other features. And Sibley’s lab at the School of Medicine is responsible for the biological testing, making sure the team stays focused on compounds that actually have the capacity to treat the cyst stage.
“The compounds we’ve started working on may not ultimately lead to a drug that works,” Sibley said. “There are no guarantees in this kind of work. But I think what we can do is establish a path forward. We can identify appropriate targets, establish the potency, and define the safety profile that you’d need for an effective clinical candidate. Then, maybe more people will pick up on our leads and do the very difficult work that is necessary to get drug candidates evaluated in humans and get one of those candidates approved as a medicine, so people don’t have to suffer and die from this devastating illness.”
