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Researchers get to heart of tropical disease

A new study found that mice lacking a gene crucial to the normal functioning of their immune systems didn't become ill when they were exposed to a pathogen that causes a horrendous infection in the liver and the spleen.

The pathogen, called Leishmania donovani, infects certain internal organs. The parasite causes visceral leishmaniasis which, if left untreated, is almost always fatal. Cases in the United States are extremely rare, but the disease, which is transmitted through the bite of a sand fly, is common in tropical and subtropical countries such as Iraq, Iran and Afghanistan.

Leishmania donovani in a bone marrow cell. Image credit: [CDC/Dr. L.L. Moore, Jr (PHIL #468), 1969. via Wikipedia.]

The finding may lend insight into creating new drugs to treat different diseases that affect the liver, said Abhay Satoskar, the study's lead author and an assistant professor of microbiology at Ohio State University.

The gene makes a protein called STAT1, and its production is triggered whenever the immune system senses a foreign bacterium, virus or other pathogen. STAT1 activation is a critical step in the immune system response, as this protein activates other key immune substances.

So it didn't make sense to the researchers that mice that couldn't produce STAT1 would remain healthy.

“It took us completely by surprise,” Satoskar said. “We knew from previous work that mice that lack the substances produced in response to STAT1 develop serious infections. We thought we'd see that in this study, too.”

The study appears as a Cutting Edge paper in the July 1 issue of the Journal of Immunology website.

The researchers infected groups of mice with L. donovani. Mice in one group lacked the gene that makes STAT1. Mice in another group lacked the gene that makes an immune system protein called T-bet. In a normal immune response to infection, STAT1 triggers the production of T-bet. Together, these proteins are responsible for the production of interferon gamma, an important protein that helps launch a full-blown immune system attack against foreign pathogens.

A group of mice with both STAT1 and T-bet genes intact served as a control.

About two weeks after infection, the researchers began measuring the number of L. donovani parasites in the animals' livers.

The pathogen went wild in the mice that lacked T-bet – the researchers found thousands upon thousands of the parasites in the livers of these animals.

Yet there were next to no parasites in the mice without STAT1.

“Two weeks after infection, the mice without STAT1 had 25-fold fewer parasites in their liver tissue than the normal mice, and about 100-fold fewer parasites than the mice without T-bet,” Satoskar said. “Visceral leishmaniasis never developed in the animals without STAT1 – the parasites weren't able to establish an infection in the animals' livers and spleens.”

The researchers also measured parasite levels in the livers two months after infection. Again, levels were quite high in the mice without T-bet, while normal mice and mice without STAT1 showed no sign of the disease.

While the normal mice weren't sick – they showed no physical signs of having leishmaniasis, such as inflammation of the liver and spleen – Satoskar said the parasite was still in their systems.

“Once infected, the parasite never goes away completely,” Satoskar said. “It's always hiding somewhere.”

Ironically, L. donovani thrives in the liver and spleen by infecting the very cells that the immune system uses to rid the parasite from the body. These cells are called macrophages – a kind of garbage collector for the immune system, as they clean out everything from red blood cells that have died to infectious pathogens. But enough L. donovani parasites can overtake a macrophage's ability to clean up.

“L. donovani infection failed to launch in mice without STAT1 because there weren't enough macrophages in the liver for the parasite to infect, and these are the very immune cells that are essential for successful survival and replication of Leishmania parasites in the host,” Satoskar said.

The researchers aren't suggesting that STAT1 activation should be stopped in order to prevent visceral leishmaniasis. However, they want to figure out how this protein's absence keeps macrophages from flooding into the liver during the early stages of infection.

If they can do that, it may be possible to create a drug to prevent L. donovani from infecting the liver and the spleen. Although there are medications available to treat the symptoms of visceral leishmaniasis, they can be toxic and sometimes expensive for the people who need them the most.

Satoskar conducted the study with colleagues from Ohio State, Montreal General Hospital in Montreal, Canada, and with the Harvard School of Public Health and Harvard Medical School.

This work was supported by grants from the National Institutes of Health, the National Institute of Dental and Cranial Research, the National Science Foundation and the Ellison Medical Foundation.

Abhay Satoskar | EurekAlert!
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