Sep. 2, 2003 St. Louis, Aug. 28, 2003 -- Researchers at Washington University School of Medicine in St. Louis have shown that Leishmania parasites engineered to lack molecules known as phosphoglycans do not cause disease in genetically susceptible mice. The mutant parasites did, however, survive.
The findings, published in the Aug. 29 issue of the journal Science, may provide an efficient way to study how Leishmania normally persists in the body without triggering symptoms. They also provide new insight into how the parasite causes a disease called leishmaniasis in some individuals and could potentially lead to the development of a vaccine.
"Somehow the persistent Leishmania mutant has found a 'safe' niche within the body that allows the parasite to survive without causing disease and at the same time preventing additional infection," says lead investigator Stephen M. Beverley, Ph.D., the Marvin A. Brennecke Professor and head of the Department of Molecular Microbiology. "This is exactly what happens in normal persistent infections. But we don't know what these persistent parasites look like, what kind of cell they infect or how they interact with the immune system. Our mutant parasite may help answer those questions."
An estimated 12 million people are infected with Leishmania parasites worldwide. Usually the immune system controls the infection and prevents development of leishmaniasis, a disfiguring and sometimes fatal disease. But for some people, such as those with AIDS who have a suppressed immune system, the parasites become active and trigger leishmaniasis. In fact, the disease is a common complication of AIDS in endemic regions including the Mediterranean basin and Southern Europe.
Persistent parasite infections are usually difficult to study, according to Beverley, because it can take six months to a year to establish the persistent infection before research can begin. Postdoctoral researcher and first author Gerald Späth, Ph.D, avoided this problem by developing a mutated parasite incapable of causing disease. This enabled the team to begin studying the animals about one week after infection.
They tested the engineered parasites in sand flies, which are responsible for transmitting the parasite to humans. The team also examined the parasites in immune cells called macrophages, which normally protect the body but are the cells that house the Leishmania parasites responsible for causing disease in mammals.
Compared to normal parasites, the mutants showed a 10-fold lower survival in the sand flies after three days, after which point they were completely eliminated. They also were unable to survive in macrophages.
Next, the investigators injected the parasites into mice that were genetically susceptible to leishmaniasis. As expected, the animals did not become sick, suggesting that the parasites had not survived. Surprisingly, though, parasites were in fact found in tissue samples from these mice.
"This was so unexpected that at first we didn't believe it," Beverley says. "But we and others have confirmed it."
Since the mutated parasites did not survive in macrophages, the investigators have no idea what type of cell did allow them to survive, and they are working to answer that question. They then will look for parasites in the same kinds of cells during normal infection.
"This will tell us if our mutant is a good model for studying normal persistent infections," Beverley says.
The researchers also are investigating whether the mutant parasite might help develop a vaccine against leishmaniasis, as many studies suggest that the key to parasite vaccination may lie in understanding how persistent parasites interact with the immune system.
"Those studies are early," Beverley says, "but they look promising."
Spath GF, Lye L-F, Segawa H, Sacks DL, Turco SJ, Beverley SM. Persistence without pathology in phosphoglycan-deficient Leishmania major. Science, Aug. 29, 2003.
Funding from the National Institute of Allergy and Infectious Diseases, the Deutsche Akademische Austauschdienst and the Human Frontiers Science Program supported this research.
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