Bio-Ophthalmology

Bacteria - not parasitic worms - play a critical role in causing river blindness

Researchers of infectious ophthalmological disease have finally succeeded in pinpointing the true causative agent of river blindness - a bacterium known as Wolbachia. The highly celebrated research finding may lead to a variety of new strategies for treating the disease.

Antibiotic administration of infected persons had previously been shown to provide an improved prognosis for those with the disease. Now, recent findings have shown why the antibiotics were so effective.

The filarial nematode worm, Onchocerca volvulus, brings about river blindness, also known as "onchocerciasis." The disease affects an estimated 18 million people in central Africa, parts of the Arabian Peninsula and South America.

Individuals infected with the worms may carry parasites that survive as adults for up to 14 years. The parasites generally live in nodules beneath the skin. Each adult female worm may grow up to half a metre in length and produce millions of microscopic larvae capable of migrating throughout the body to cause a variety of symptoms.

Such symptoms not only include the visual impairment that can lead to blindness. The worms also produce rashes, lesions, intense itching, depigmentation of the skin, lymphadentitis - which leads to elephantiasis of the genitals - and general debilitation.

The group responsible for the link to the Wolbachia bacteria included researchers from the University Hospitals of Cleveland and Case Western Reserve in the United States, the Bernard Nocht Institute for Tropical Medicine in Germany and the Liverpool School of Tropical Medicine in the UK. The groups findings were published in a recent edition of Science (2002;295:1892).

Of the 120 million people worldwide who are at risk from onchocerciasis, over 96% are in Africa. The disease is currently endemic in 36 countries, 30 of which are in sub-Saharan Africa with the other six in Latin America.

Of those infected, the World Health Organisation reports that approximately 6.5 million suffer from severe itching or dermatitis and close to 270,000 individuals have become totally blind with nearly twice that number suffering some degree of visual impairment.

The infectious life cycle of the parasite involves two hosts - humans and black flies. Microscopic larvae, also known as microfilariae, are produced under the skin of infected individuals and carried from person to person by the Simulium damnosum fly.

The fly lays its eggs in the waters of fast-flowing rivers, thus giving the disease its name. Once the adult worms emerge, the fly may live for up to four weeks. During those four weeks, the black flies can cover hundreds of miles in flight to infect new human hosts.

Researchers were alerted to the potential role of a bacterium in the disease pathology through the observation that patients treated with antibiotics were less likely to develop full characteristics of the disease.

The international research team, led by Dr Amélie V Saint André and Dr Eric Pearlman, used a mouse model of corneal inflammation to mimic human river blindness and determine what was causing the disease pathology associated with filarial nematodes.
Through a series of experiments demonstrating successively finer detail, the team was able to show the mechanisms responsible for many of the more severe symptoms of onchocerciasis.

Starting with a similar approach to that used by such 19th century 'fathers' of medical microbiology as Louis Pasteur and Robert Koch, the researchers injected mice with extracts from two types of nematodes, one pre-treated with antibiotics and the other untreated.

Mice injected with extracts from antibiotic-treated worms showed far lower signs of disease symptoms than those injected with untreated extracts, thus convincingly demonstrating that it was the bacteria that were causing the problem.
Working from such clues, the research team rightly guessed that if bacteria were involved they ought to look for a smoking gun, specifically a smoking gun known as lipopolysaccharide, more commonly known as LPS.

Often found on the cell walls of bacteria, LPS has been known to induce severe immune reactions in host organisms causing inflammation similar to that observed in patients with river blindness.

To check if LPS was mediating the disease pathology in the mouse model of corneal inflammation, the researchers again injected animals with extracts from nematodes recovered from patients.
The extracts were injected into two types of mice, one sensitive to LPS and the other non-reactive to LPS due to a mutation in a human host gene known as TLR4, essential to host cell response against bacterial LPS.

The results were clear. Animals injected with infectious nematodes only developed disease symptoms if their TLR4 gene was intact. In other words, it wasn't so much the bacterial LPS causing the disease as an over-reaction by the host immune defences.

Finally, knowing that TLR4 regulates the development of keratitis associated with river blindness, the researchers looked at the degree of immune cell recruitment in the cornea in LPS sensitive and non-responsive mice.

Only the LPS sensitive animals showed an inflammatory response, again confirming the role of bacteria in the disease in addition to the role of the innate immune system.
The current drug being used for the treatment of river blindness, ivermectin, manufactured by Merck & Co under the trade name Mectizan, is capable of reducing the numbers of skin microfilariae in infected people. However, patients must take the drug for up to 15 years - and even then, the drug does not kill the adult worm.

The recent findings clearly demonstrate that the real target to treat river blindness is the Wolbachia bacterium and that treatment may involve as little as a single course of antibiotics such as doxycycline. As adult nematode worms are incapable of reproduction without the bacteria, antibiotic treatment may represent a far quicker alternative to ivermectin.

Conquering river blindness, however, means more than just curing disease. Take the example of the Volta basin of West Africa. No sooner had the World Health Organisation helped eradicate river blindness in that region than did the UN's Food and Agricultural Organisation launch an initiative to ensure resettlement and sustainable farming in the region.

Such tales illustrate how the successful treatment of an infectious disease in the developing world can produce real and immediate benefit.
Such tales also demonstrate how much we owe to World Health Organisation officials and volunteers who have toiled at the coalface over the past 20 years to fight blindness worldwide.

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