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A New Gold Standard: Improved Animal Model Could Speed Drugs for Chagas’ Disease

This child from Panama is suffering from Chagas’ disease manifested as an acute infection with swelling of the right eye
This child from Panama is suffering from Chagas’ disease manifested as an acute infection with swelling of the right eye.
CDC/Dr. Mae Melvin.
For the first time, researchers have cured mice chronically infected by Trypanosoma cruzi (T. cruzi) parasites. NIAID grantee Rick Tarleton, Ph.D., of the University of Georgia, says the advance provides investigators with a “gold standard” animal model for testing the efficacy of candidate drugs against T. cruzi, which, when transmitted to humans by so-called kissing bugs, cause Chagas’ disease.

A Disease with a Long Fuse

Chagas’ disease is named for the Brazilian physician Carlos Chagas (pronounced SHA-gus), who published the first description of the ailment in 1909. According to the U.S. Centers for Disease Control and Prevention, between 8 and 11 million people in Mexico, Central and South America have Chagas’ disease. Most people do not know they are infected.

T. cruzi parasites are spread primarily through the droppings of some species of kissing bugs and related “assassin” bugs. The bugs emerge at night and tend to bite sleeping people on the face, and defecate at the same time as they bite. A bitten person may rub parasite-laden feces into the bite or into the eyes or mouth, thereby becoming infected.

The initial (or acute) phase of infection often results in no more than swelling at the site of the bite, sometimes accompanied by fever and body aches. After a few months, the infection enters its chronic phase.

A majority of people will suffer no ill effects from chronic T. cruzi infection. But about one-third of those infected develop serious cardiac or intestinal complications, often decades after the initial infection. According to the World Health Organization, about 13,000 people die of Chagas’ disease each year.

Curing Mice of Chronic Chagas’

The only two drugs available to treat Chagas’ disease have significant shortcomings. They must be taken every day for at least 2 months; they can cause severe side effects; and they do not always work. Typically, notes Dr. Tarleton, Chagas’ disease is treated only in its acute or early chronic phases, in part because no definitive test exits to tell whether the drugs have completely eradicated the parasites. (T. cruzi parasites can rarely be detected in the blood after the acute phase, regardless of whether a person has been treated.)

Mice, like humans, are natural hosts for T. cruzi parasites. This makes them an excellent model for understanding human Chagas’ disease, says Dr. Tarleton. In their recent study, he and his colleagues treated mice with two courses of a standard Chagas’ disease drug. Some of the mice received treatment several hundred days after infection, which, given a mouse’s normal lifespan of about 3 years, is the equivalent of treating late chronic Chagas’ disease in humans. The scientists documented a complete elimination of T. cruzi from the chronically infected mice.

Not only did this study show that a chronic parasitic infection could be cured, it also provides scientists with a well-defined model of mouse immune system responses that are indicative of a cure. “It’s a huge step forward,” says Dr. Tarleton, opening the way to use of the model for evaluating new candidate drugs. Now, for example, researchers can directly compare the standard treatment with newly developed drug candidates.

Telltale T Cells

After the mice were cured, the scientists detected the dominance of a subset of immune cells called central memory T cells in the animals’ blood. An increase in that subset of memory T cells does not occur until after the body has cleared an infection, so finding them proved that T. cruzi had been eliminated. This discovery is likely to be very useful in assessing whether Chagas’ disease has been cured in humans as well, notes Dr. Tarleton. By looking for T. cruzi-specific memory T cells in a treated person’s blood, he explains, doctors could tell whether or not the parasites had been wiped out by the drug therapy. Dr. Tarleton is now working with colleagues in Argentina to test whether human immune responses (such as the production of memory T cells) following Chagas’ disease treatment mirror those seen in mice.

Reference: JM Bustamante et al. Drug-induced cure drives conversion to a stable and protective CD8+ T cell memory response in chronic Chagas disease. Nature Medicine DOI 10.1038/nm1744 (published online April 20, 2008).

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Last Updated April 23, 2009