River blindness, a devastating tropical disease that affects 18 million people in Africa, the Arabian peninsula, and Latin America, is caused by parasitic worms that burrow into the skin and release millions of tiny offspring that spread throughout the body. But, the worms themselves probably aren't the main culprits behind the disease, says an international team of scientists.
Instead, it's the worms' cargo of Wolbachia bacteria that provokes the body's severe inflammatory response, leading to blindness and serious skin disorders, the researchers report in the 8 March issue of the journal Science, published by the American Association for the Advancement of Science.
Pinpointing bacteria as the direct factor behind the disease's virulence may suggest new therapies for combating river blindness, especially since recent studies in infected humans have shown that the bacteria can be killed by the common antibiotic doxycycline.
River blindness is the second leading infectious cause of blindness in the world. It is spread to humans by the bite of black flies infected with the parasitic worm Onchocerca volvulus. The battle against river blindness is taking place on two fronts at the moment, with programs to control the spread of the black fly and to freely distribute an anti-worm medicine called ivermectin.
Onchocerca larvae deposited by the fly's bite burrow into the skin, where they mature and eventually send out tiny offspring called microfilariae that can migrate through the skin to the eye. When the microfilariae die, they trigger a severe immune response, resulting in eye inflammation and eventual vision loss.
Onchocerca don't travel alone on this journey: At all stages of their life cycle, the worms contain Wolbachia bacteria that appear to be essential companions. Recent research by two of the Science authors, Achim Hoerauf and Lars Volkmann of the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany, suggests that the worms need Wolbachia to reproduce successfully.
With the close connection between worm and bacteria in mind, the Science researchers devised experiments to uncover Wolbachia's exact role in the development of river blindness. Using a mouse model for the disease, the researchers infected mice with extracts taken from worms treated with doxycycline (which contain relatively few Wolbachia) and with extracts from nontreated worms (with a normal Wolbachia load).
Mice exposed to the treated extracts showed significantly less thickening and haze of the eye's cornea, and less signs of inflammation such as infiltration of white blood cells into the cornea, compared to mice infected with the untreated extracts.
"These data show that Wolbachia itself has a major role in the disease's pathology," says Pearlman.
The body's innate immune response also plays a large part in how the disease progresses, according to the researchers. Mice lacking a key immune cell receptor molecule called TLR4 showed fewer signs of eye inflammation when exposed to Wolbachia-laden worm extract.
These mice also produced smaller amounts of certain other immune molecules and proteins that are normally recruited to fight infection, suggesting that TLR4 might regulate Wolbachia-triggered inflammation by controlling the expression of these immune molecules.
Pearlman and colleagues conclude that antibiotic treatment of Wolbachia may help reduce the severity of the symptoms of river blindness in already-infected individuals. In addition, targeting Wolbachia could prevent the spread of Onchocerca parasites, say the authors.
Recent studies have shown that Wolbachia-killing doxycycline treatments in infected humans also sterilize their worm hosts, breaking the cycle of ever-spawning microfilariae. Current ivermectin treatments, by comparison, only deplete the number of skin microfilariae for a few months, requiring continued doses to keep the parasite under control.
The other members of the research team include Amélie v. Saint André, Nathan M. Blackwell, Laurie R. Hall, Amy G. Hise, Jonathan H. Lass, and Eugenia Diaconu of University Hospitals of Cleveland and Case Western Reserve University, Norbert W. Brattig of Bernhard Nocht Institute for Tropical Medicine, and Mark J. Taylor and Louise Ford of the Liverpool School of Tropical Medicine in Liverpool, UK. This research was supported in part by the National Institutes of Health, German National Merit Foundation, the European Union, the German Research Foundation, the Wellcome Trust, Fight For Sight, and Research to Prevent Blindness Foundation.
Materials provided by American Association For The Advancement Of Science. Note: Content may be edited for style and length.
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