August 25, 2008

Immune Cells Help Tropical Parasites Evade Death

Photo of a sandfly Leishmania parasites enter the bodies of humans and other animals through sand fly bitesDr. Frank Collins, CDC.

Tiny parasites that cause the tropical disease leishmaniasis may take advantage of the body’s initial defenses by hiding and surviving inside the fast-acting immune cells sent to devour them, according to a new study. The research provides a new view of the earliest stages of Leishmania major infection, which begins with a bite from an infected sand fly.

Leishmaniasis occurs in nearly 90 countries, mostly in tropical regions. The most common form of the disease, called cutaneous leishmaniasis, causes painful skin sores that can take months to heal and leave behind permanent scars.

Scientists have long known that Leishmania parasites enter the bodies of humans and other animals through sand fly bites. Then, according to conventional wisdom, the parasites establish a long-term infection inside immune cells called macrophages, where they multiply, break free and get taken up by other macrophages. The new study, published in the August 15, 2008, issue of Science, provides evidence for an additional, intermediate step, in which the parasites temporarily hijack microbe-eating immune cells called neutrophils.

To get a better understanding of the initial stages of infection, scientists from NIH's National Institute of Allergy and Infectious Diseases (NIAID) used deep-tissue imaging to look beneath the skin of mice and watch in real time as animals' immune cells responded to sand fly bites and the parasites. To more easily track immune cell movements, the researchers studied transgenic mice with green-glowing neutrophils. Red-glowing, genetically engineered strains of L. major allowed easy viewing of the parasites.

The research team, led by Drs. Nathan C. Peters and Jackson Egen, showed that sand fly bites and other minor skin injuries caused neutrophils to rush to the wounded area. In less than an hour, bites from both infected and uninfected sand flies summoned a growing number of neutrophils to the damaged tissue. The neutrophils that swarmed around infected bites efficiently engulfed the parasites. But unlike many other infectious organisms that die inside neutrophils, L. major parasites appear to have evolved in a way to evade death, actually surviving for long periods of time inside the neutrophils.

Eventually, the researchers showed, the neutrophils died and released viable parasites, which were engulfed by macrophages to continue their life cycle. Within a week after the sand fly bite, most of the infected cells were macrophages rather than neutrophils.

The researchers also found that neutrophil-depleted mice were more resistant to L. major infection from sand fly bites, suggesting that neutrophils are critical to the parasite's survival.

“This work changes the textbook picture of the lifecycle of the leishmaniasis parasite, identifying the inflammatory cell known as the neutrophil as the predominant cell involved during the initiation of infection,” says NIAID Director Dr. Anthony S. Fauci.

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