One of the most common human parasites, Toxoplasma gondii, uses a hormone lifted from the plant world to decide when to increase its numbers and when to remain dormant, School of Medicine researchers have found.
The scientists report in Nature that they successfully blocked production of the molecule, known as abscisic acid (ABA), with a plant herbicide. Low doses of the herbicide prevented fatal T. gondii infection in mice.
David Sibley
“As a target for drug development, this pathway is very attractive for several reasons,” said author L. David Sibley, Ph.D., professor of molecular microbiology. “Because of its many roles in plant biology, we already have several inhibitors for it. Also, the plant-like nature of the target decreases the chances that blocking it with a drug will have significant negative side effects in human patients.”
T. gondii‘s relatives include the parasites that cause malaria, which also appear to have genes for ABA synthesis. The new findings may explain an earlier study where a group of researchers found that the same herbicide inhibits malaria.
Infection with T. gondii, or toxoplasmosis, is perhaps most familiar to the general public from the recommendation that pregnant women avoid changing cat litter. Cats are commonly infected with the parasite, as are some livestock and wildlife. Humans also can become infected by eating undercooked meat or by drinking water contaminated with spores shed by cats.
Epidemiologists estimate that as many as one in every four humans is infected with T. gondii. Infections are typically asymptomatic, only causing serious disease in patients with weakened immune systems. In some rare cases, though, infection in patients with healthy immune systems leads to serious eye or central nervous system disease, or congenital defects in the fetuses of pregnant women.
Scientists have known for about a decade that protozoan parasites like T. gondii and those that cause malaria contain many plant-like pathways, or groups of genes or proteins put to use for a particular biological task. An earlier revelation led to ongoing efforts to develop drugs that block plant-like proteins parasites use to synthesize metabolically important structures or compounds. However, until this study, no one had found the parasites using a plant-like protein for signaling purposes.
“Signals are sometimes even better targets for drug development than biosynthetic pathways,” said Sibley. “Taking out a biosynthetic pathway means you take away one thing from the parasite. But if you can successfully disable a key signal, this may potentially disrupt many more aspects of the parasite’s metabolism.”
Kisaburo Nagamune, Ph.D., formerly a postdoctoral fellow in Sibley’s laboratory, found the ABA pathway in T. gondii while searching the parasite’s genome for pathways linked to calcium signaling. A series of experiments led by Nagamune, now an assistant professor at Tsukuba University in Japan, showed that ABA helps the parasites control their reproductive cycle by communicating with each other in the host cell. When they sense high enough levels of ABA, the parasites break out of host cells; otherwise, they stay in the host cell and remain dormant.
With help of online databases and botanists at the Donald Danforth Plant Science Center in St. Louis and elsewhere, researchers quickly identified a class of herbicides that block ABA production and that are already in use commercially and screened for low toxicity to animals.
Scientists tested one of those herbicides against toxoplasmosis, labeling the test parasites with the firefly luciferase protein. Whole animal imaging showed that treatment with the herbicide reduced the number of parasites in infected mice during the initial infection and also reduced the chronic burden.