On the fast-flowing rivers of equatorial Africa, a stout, stubby, black, biting fly named Simulium lays its eggs. The insect’s proboscis is short and sharp adapted for piercing skin in livestock and humans. Through that subcutaneous wound the fly deposits infective larvae, which develop into adult worms in about a year. These fly-borne parasites, Onchocerca volvulus, are the direct perpetrators of African river blindness in humans.
Some 18 million men, women and children are infected, and 270,000 go completely blind. Twice as many suffer impaired eyesight. In fact, that black fly’s vision-destroying gift is the second leading cause of infectious blindness in the world after trachoma. And besides its wide swath across western Africa, the parasite also infects areas of Central America presumably imported by European slave traders in the 16th century.
The thread-like female worms, sometimes a foot long, curl up and bed down in nodules under the skin, where they may live for 15 years. The male parasites find their way to impregnate them. Mature worms migrate to the eye.
“River blindness is a huge problem in Africa,” observed parasite immunologist Eric Pearlman. “A generation ago, 10 percent of West African villagers near the rivers were blind as a result of this disease. Villages were being abandoned, and the social and economic effects were devastating.”
Today’s Science, dated March 8, 2002, carries a paper titled: “The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness.” Its senior author is Eric Pearlman of the department of ophthalmology at Case Western Reserve University in Cleveland.
“The overall finding of this paper,” Pearlman told BioWorld Today, “is that bacteria present in these parasites seem to be largely responsible for the pathologies. Rather than being parasite products involved in causing the disease, the study in Science shows that the Wolbachia bacteria have a major role for the bacterial products. These bacteria have been known to be present in the worms for maybe 30 years. People speculated on what the Wolbachia might be doing, but nobody knew until the last few years, when molecular biologies became available, and investigators could look at this bacterium more closely.”
Bacterium’s World Record Bugging Bugs
“So we did such studies,” Pearlman added, “and determined which parasites harbor the Wolbachia bacteria and which don’t. Wolbachia infect something like 80 percent of insect species,” he pointed out. “That makes it perhaps the most ubiquitous infectious bacterium on earth. It is not a human or a mammalian microorganism. In this river blindness case, it’s a parasite of the parasites, and a parasite of insects, including spiders, beetles, crickets, bedbugs, cockroaches and ants, to name a few.
“The adult worms that give rise to the larvae,” Pearlman explained, “crawl through the skin. Then the larvae are picked up by the black flies, while they’re in the skin. The Walbachia that’s in the worm never goes to the insect. There’s no transfer of the bacteria from one species to the other. The worms can get into the eye as well,” he said, “into the cornea. And we think it’s when the worms die that there is a release of worm product and bacterial product in the eye. It’s a host response that leads to corneal inflammation, loss of vision and ultimately blindness.
“Wolbachia appears to be essential for embryogenesis,” Pearlman went on, “which certainly involves these filarial, thread-like worms that cause the disease. How the bacterium does it in insect species, or in these worms - is not known. So our co-author, Achim Hoerauf in Germany, treated the worms with antibiotics in a culture dish, in experimental animals, and in patients. When he took out the worms he could see that the embryos they had were stunted. Hoerauf’s group is already treating patients in West Africa, specifically in Ghana, with doxycyclin, showing that it’s effective in reducing the number of larvae that migrate in through the skin, thereby reducing transmission.
“Our study in Science,” Pearlman pointed out, “is the first direct evidence that because the Wolbachia are involved in development of disease, doxycyclin treatment should also have a beneficial effect on its pathology, because it gets rid of the bacteria. If the worms in the skin or eye are dying, then in theory you should have less disease, less inflammation. What doxycyclin essentially did was render these worms sterile.”
Ivermectin is an antihelminthic agent, best known as a remedy for canine heartworm. But it also destroys Onchocerca microfilaria, the river blindness parasite. “When ivermectin became available, and was tested in the mid-1980s to see efficacy,” Pearlman recounted, “then Merck & Co. Inc., the drug’s maker once it presumably realized that the river blindness people who would be receiving ivermectin couldn’t pay for it anyway agreed to donate the drug philanthropically, literally billions of doses over the last 20 years.”
Pushing Contact Lenses’ Extended Wear
“So ivermectin is distributed once a year,” Pearlman went on. “It does not kill the adult worms, only the larvae, so the adults continue to produce microfilaria. That’s why recipients have to be treated every year. But this eleemosynary ivermectin program has been going on since the mid-1980s, and the level of transmission is greatly reduced in 11 countries of West Africa, although there are still over 100 million people infected.
“We’re focusing an blindness, which is the most dramatic aspect of this disease,” Pearlman said. “We have a mouse model of keratitis corneal inflammation. We place some parasite antigens into their eyes and monitor the corneal response. Our initial conclusion: In the absence of Walbachia, there’s very little disease.”
He cites two putative industrial spin-offs from focusing on corneal inflammation: The side effects of laser surgery to correct vision and complications of contact lens wear. “We have done some studies on this,” Pearlman recalled, “indicating that the mechanisms appear to be somewhat similar to our river blindness work. We have a paper in preparation showing that bacterial lipopolysaccharides [LPS] can directly induce similar responses. We used LPS from Pseudomonas species, bacteria commonly associated with corneal ulcers caused by extended wear of contact lenses. That would likely be the application in this country,” he concluded, “rather than the river blindness itself.”