IU research team works to discover new toxoplasma treatments
July 25, 2013
Take you, me and someone sitting near you at lunch. Chances are at least one of us has a parasite tucked away in their brain -- alive but safely inactivated by the immune system.
Bill Sullivan, Ph.D., Ron Wek, Ph.D., Christian Konrad, Ph.D., and Sherry Queener, Ph.D., all researchers at the IU School of Medicine, study this parasite — toxoplasma — a single-celled protozoan that infects one in every three people in the country.
Although extremely common, it's normally not fatal, or even noticed. Healthy adults infected with the parasite usually mount a strong immune response, forcing it into a latent cyst form.
At the same time, it’s permanent. Neither the body’s immune system nor any drugs can remove the parasite after it hunkers down in protective cysts.
And if the immune system is compromised — such as in cases of HIV or chemotherapy — the parasite can emerge from its latent state and resume replicating, creating a serious and sometimes fatal infections as well as posing a risk of congenital birth defects in pregnant women.
For these reasons, and more, “we need to find new treatments that will enable us to control or prevent these infections that can occur when the toxoplasma parasite emerges from its dormant state,” said Dr. Sullivan, associate professor of pharmacology and toxicology at the IU School of Medicine.
The challenges are many. Preventing an initial toxoplasma infection is difficult because the parasite is pervasive in vertebrates and has made it into the food supply — another reason to cook meat thoroughly. One of the most common carriers is the house cat, which is why pregnant and soon-to-be pregnant women are cautioned to let someone else take care of the litter box.
But a new discovery may change the parasite's intractable nature. Dr. Sullivan and his team recently published a report that they’ve found guanabenz, a drug used to treat hypertension, may work as a “sleeping pill” to keep the toxoplasma parasite under control.
In a study published in the April 2013 edition of Antimicrobial Agents and Chemotherapy, the researchers tested the effects of guanabenz on parasites in cell culture and found that it inhibited parasite replication, induced the parasite to convert to its latent state and inhibited the parasite from reactivating into its infectious state. The drug also significantly extended the lives of mice infected with a fatal dose of toxoplasma.
The team focused on guanabenz because it targets a particular protein — eIF2 initiation factor — that is key to cells’ ability to make proteins. In times of stress, such as when the body’s immune system is attacking toxoplasma, the parasite’s eIF2 protein undergoes a chemical change — a phosphorous molecule is added — and protein production drops dramatically, said Dr. Konrad, a post-doctoral investigator and the paper’s first author.
Guanabenz, it turns out, works to keep that phosphorous molecule attached, in turn keeping the parasite inactive.
The next step, before taking the drug to clinical testing, is to test the effectiveness of the drug in preventing reactivation of the parasites in mice.
“The great thing about guanabenz is that it’s already approved for use in hypertension. It has a good safety profile, it can reach the brain and it’s well absorbed when taken as a pill,” Dr. Sullivan said.
“If we can emulate what we’ve done in vitro here in the clinic, which is where this would go next, we could possibly have a preventive drug to administer to heart transplant or HIV patients that would minimize or stop the reactivation of this infection.”
The toxoplasma parasite is also a good study subject to better understand a similar parasite that causes another intractable disease -- malaria -- which is notoriously difficult to work with in the laboratory.