Could antibiotics cure river blindness?



River blindness, affecting 200 million people in rural Africa and to blame for hundreds of thousands of cases of preventable blindness, may be caused by a bacterium. If so, it could in principle be controlled by antibiotics — according to a recent paper in Science (2002;295: 1892-5).

This is something of a shock, because the textbook explanation of the disease is infection by filarial worms, Onchocerca volvulus, cured by annual treatment with ivermectin, a drug which kills the young microfilariae the adult worms produce in the body. But it's not the worms themselves, but the bacteria they carry, that cause the blindness in the disease, according to a team of researchers from the US, Germany and the UK.

Onchocerca worms are transmitted by blackflies which breed in fast-flowing rivers. After a person is bitten by an infected fly, the worms grow into adults, forming a nodule the size of a grape under the skin. There they live for over ten years, breeding and creating streams of young "microfilariae" or "little threads", which spread through the body, entering and irritating the patient's skin, where they are ready to be picked up by another blackfly to complete the cycle.

Blindness follows when the microfilariae migrate to the eyes. There, accumulating and dying over many years, they lead to the transparent cornea of the eye turning milky, eventually becoming opaque and causing complete blindness. But precisely how they made the cornea milky was not known — until now. It seems that a bacterium in the worm, Wolbachia, does most of the damage, rather than the worm itself.

Last year a team of scientists in Germany discovered that Wolbachia bacteria were an essential to the worms: without them the worms cannot produce microfilariae. Wolbachia also turned out to be essential for the filarial worms that cause lymphatic filariasis, Brugia malayi and Wucheria bancrofti.

Then the question arose: how important are the bacteria to blindness? To answer it, the German group, at the Hamburg School of Tropical Medicine, sent extracts of adult worms (which patients are pleased to get rid of, if a surgeon is available to cut off the nodules) to Eric Pearlman at Case Western Reserve University at Cleveland in the United States. In fact they sent two samples: one including the Wolbachia naturally present in the worms, and one without — after treatment with doxycycline, an antibiotic.

In Pearlman's laboratory, the extracts were injected into the corneas of mice, a model for river blindness. The corneas were affected by both extracts, but much more so when the Wolbachia were present. The researchers also showed how the corneas of certain mice, with a precise mutation that makes them insensitive to bacterial endotoxin, were not affected by either extract. So it seems that the endotoxin of the bacterium Wolbachia is causing more of the blindness of onchocerciasis than the worm Onchocerca volvulus.

So far, good science; but what about the impact on patients? The trouble is that a course of antibiotics would require a six-week, daily treatment. "Unfortunately it's completely impractical, unless the antibiotic regimens can be simplified" said Hans Remme of the Tropical Disease Research Programme at WHO. It has been a massive exercise to get single doses of ivermectin annually to the remote communities that need it, and six-week courses of anything would be far more difficult, he says.

"Even so, if antibiotics were the perfect intervention we would try to develop an appropriate distribution method" Remme says. "But there are risks of adverse reactions, and important exclusion criteria such as children below eight years old, and pregnant and lactating women. These prevent large- scale use and elimination of the parasite reservoir after the six weeks of intervention", says Remme.

One of the authors of the mouse paper, Mark Taylor of the Liverpool School of Tropical Medicine, argues, however, that "those ivermectin treatments will have to go on for more than 20 years, because the adult worms stay alive. Antibiotics could reduce this period by permanently sterilizing the adult worms, and at the same time remove the cause of the blindness. And we are planning trials to find the minimum period of antibiotic therapy, and to find out what effect antibiotics have on the other filariases."

Remme doesn't completely rule out antibiotics either. "We are thinking about using them to snuff out localized outbreaks, in areas that have previously been cleared", he adds.

Robert Walgate, Bulletin

World Health Organization Genebra - Genebra - Switzerland