Bloodstream malaria infections in mice successfully cleared

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University of Iowa researchers and colleagues have discovered how malaria manipulates the immune system to allow the parasite to persist in the bloodstream. By rescuing this immune system pathway, the research team was able to cure mice of bloodstream malaria infections. The findings, which were published Dec. 11 in the Advance Online Publication of the journal Nature Immunology, could point the way to a new approach for treating malaria that does not rely on vaccination and is not susceptible to the parasite’s notorious ability to develop drug resistance. “Malaria is chronic, prolonged infection and the host immune defense has a tough time clearing it and sometimes it never clears it,” says Noah Butler, PhD, UI postdoctoral research scholar and lead study author. “We’ve determined that this prolonged infection actually drives dysfunction of the immune cells that are supposed to be fighting the infection, which in essence allows further persistence of the parasite infection.” More specifically, the study showed that the malaria parasite stimulate these key immune cells (known as CD4+ T cells) so that they continuously express molecules called inhibitory receptors. Under normal circumstances, these molecules help to “apply the brakes” to the immune response and prevent over-activation that can be harmful. However, by keeping the mechanism turned on, the malaria parasite damps down the immune response significantly, reducing the T cells’ ability to fight the parasite and allowing it to persist.

Importantly, the team also showed that blocking the action of the inhibitory receptor molecules resulted in immediate and complete clearance of the malaria parasite. “When we blocked the function of these molecules, we took the brakes off the host’s immune response and everything got better — the overall immune response was dramatically improved and there was immediate control and accelerated clearance of the parasite,” says John Harty, PhD, professor of microbiology and pathology at the UI Carver College of Medicine and senior study author. “These findings suggest an alternative approach for the treatment of existing malaria infection.” More than half the world’s population is at risk of malaria, a mosquito-borne parasite that causes anemia and high fever and which can persist for weeks or months. There are more than 200 million cases of malaria each year and an estimated 800,000 children die from malaria annually. Harty notes that the current study was done in mice and it is not yet known if the same approach will work in humans. However, two factors suggest the strategy may have potential. First, drugs that block inhibitory receptor molecules are available and currently being tested as cancer therapies. And second, the UI team found that malaria infection in humans does lead to increased expression of inhibitory receptors on CD4+ T cells suggesting that these molecules could represent a viable target for human therapies.

Science Daily
January 10, 2012

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