BACTERIA, NOT WORMS ARE THE MAIN CAUSE OF RIVER BLINDNESS
31 March 2002 - Case Western Reserve University

Instead, it is the worms' symbiotic cargo of Wolbachia bacteria that provokes the body's severe inflammatory response, leading to blindness and serious skin disorders, the researchers report Science, published by the American Association for the Advancement of Science.

"The results presented here show that clearance of the bacteria with antibiotics may reduce and prevent river blindness," says Science senior author Eric Pearlman, Ph.D., associate professor of medicine and ophthalmology at CWRU and UHC.

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. 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, M.D., 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 cells into the cornea, compared to mice infected with the untreated extracts.

"These data show that Wolbachia itself has a major role in the pathology of the disease," 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.

James Kazura, M.D., director of the division of geographic medicine at CWRU and UHC, says the findings "offer a novel insight to potential approaches to develop a vaccine and, more fundamentally, they offer potential insights of how the genes of the human system have evolved over time." He said the genes that respond to this disease are the same ones found in many primitive organisms, such as flies, and these genes have been evolutionary conserved in humans over time.

The battle against river blindness is taking place on two fronts at the moment, with World Health Organization- and World Bank-sponsored programs to control the spread of the black fly and to distribute an anti-worm medicine called ivermectin.

Pearlman and colleagues conclude that antibiotic treatment of Wolbachia may help by reducing the severity of the symptoms of river blindness in already-infected individuals. As Hoerauf's studies also show that the bacteria can be killed by the common antibiotic doxycycline, pinpointing bacteria as the direct factor behind the disease's virulence may suggest new therapies for combating river blindness. This is in addition to targeting Wolbachia to prevent the spread of Onchocerca parasites, as suggested by Hoerauf's research.

Pearlman and colleagues at the CWRU School of Medicine and UHC have been striving to understand the disease mechanisms of river blindness for the past eight years. To study the course of the disease, Pearlman has developed animal models that reproduce the characteristics of the human onchocerciasis. Through the CWRU/UHC Visual Sciences Research Center, the only federally funded center of its kind in Ohio, he collaborates with clinical researchers such as Jonathan Lass, M.D., the CWRU Charles I Thomas Professor of Ophthalmology and UHC chair and director of ophthalmology. In support of Pearlman's work, the research center provided important core laboratory facilities, such as histologic and digital imaging services, supported by its grant from the National Eye Institute.

Lead author of the study is Amelie v. Saint Andre, who is a German medical student in a program, established by Paul Lehmann, Ph.D., CWRU associate professor of pathology, which brings top German medical students to CWRU to conduct research. Others authors: Nathan M. Blackwell, Ph.D., Laurie R. Hall, D.Sc., and Eugenia Diaconu, D.V.M., of Pearlman's lab; Amy G. Hise, M.D., of James Kazura's, M.D., lab at CWRU and UHC; Norbert W. Brattig, Ph.D., of Bernhard Nocht Institute for Tropical Medicine, and Mark J. Taylor, Ph.D., and Louise Ford of the Liverpool School of Tropical Medicine in Liverpool, UK. This research was supported in part by the National Eye Institute, German National Merit Foundation, the European Union, the German Research Foundation, the Wellcome Trust, Fight For Sight, and Research to Prevent Blindness Foundation.

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