For a tiny microorganism that can survive only within the cells of other creatures, the bacterium Wolbachia packs an impressive punch. Nestling in the reproductive tissues of its invertebrate hosts, from insects and spiders to crustaceans, Wolbachia can cause infertility, turn male embryos into females, kill male embryos at an early stage, and turn females on to virgin birth.

Wolbachia has taken the scientific world by storm. Field research has shown that it is probably the commonest parasite on earth. It infects perhaps 20 per cent of all insect species, as well as spiders, mites and crustaceans. Even parasitic wasps and worms have now been found to harbour their own parasitic Wolbachia - a real case of the biter bit.

Dr Steven Sinkins, Head of the Vector Research Group at the Liverpool School of Tropical Medicine, has watched interest in this extraordinary organism snowball. Dr Sinkins is studying Wolbachia in the mosquito Culex. "It was in Culex that Wolbachia was first discovered, in 1924," he points out, "and in the 1950s, it was in Culex that scientists found that crosses between certain strains were almost always infertile - the eggs that resulted from a mating did not develop. The effect is known as ‘cytoplasmic incompatibility’."

Twenty years later, Yen and Barr at the University of California made the connection. They cured the Wolbachia infection with antibiotics and showed that sterility always occurred when an infected male mated with an uninfected female - if both parties were infected with the same Wolbachia strain, the eggs were perfectly viable.

This bizarre phenomenon turns out to make perfect sense from the bacterium’s point of view: by giving infected females a strong reproductive advantage, Wolbachia ensures its own continuing success. Now, even more strange reproductive quirks have been laid at Wolbachia’s door (see box below), all of which increase the frequency of infected females carrying Wolbachia in their eggs.

The strategy is highly successful: Wolbachia infections can spread like wildfire through uninfected insect populations in the field. "And that's generated a great deal of applied interest," says Dr Sinkins. "If we could transform Wolbachia to carry ‘useful’ genes, the bacterium could prove a powerful tool with which to spread those genes through mosquito populations. The obvious examples are genes to block the transmission of viruses and malaria parasites, as well as filarial nematodes."

Dr Sinkins is trying to unravel the molecular mechanisms that underlie the complex control of cytoplasmic incompatibility, to understand precisely how Wolbachia and Culex systems interact and to locate the genes responsible. He has also investigated more complex crosses, for example using male mosquitoes infected with two Wolbachia strains. These mosquitoes fail to produce offspring when crossed with females harbouring either one of the Wolbachia strains. This is good news, as it increases the likelihood that disease control genes could be spread through a population.

Wolbachia and the worm

Wolbachia, he has to confess, wasn’t on fellow Liverpool researcher Dr Mark Taylor's mind in 1999. A Wellcome Senior Research Fellow in Basic Biomedical Science, he and his group were trying to discover the molecular basis of the inflammatory reaction caused by Brugia malayi (a parasitic nematode worm). "We were looking for a molecule and found an entire organism!"

What Dr Taylor discovered was that the nematode was not in fact the guilty party. The damaging inflammation was triggered by toxins from Wolbachia when it was released from the worm. Wolbachia also turned out to be responsible for the acute inflammatory responses some heavily infected patients suffer when given antifilarial drugs such as DEC or ivermectin.

The impact of these discoveries was electrifying. If bacteria were to blame, then antibiotics might offer a solution. As Dr Taylor explains: "This is one of those very rare situations when you can go straight from a basic biological experiment in a laboratory to clinical trials in the field." In Tanzania, they are now testing the effect of a course of antibiotics on filariasis, and the signs are very promising.

Dr Taylor, together with colleagues in Germany and the USA, has also shown that Wolbachia is responsible for activating the inflammation that leads to river blindness. The nematode host involved in this cruel filarial disease, Onchocerca volvulus, can live for more than ten years and release millions of young larvae over this time. These microfilariae can migrate to the eye, causing major scarring and blindness. Again, it turns out that the root cause is not the worm but Wolbachia.

The discovery has had another significant impact. "Antibiotics not only reduce the inflammatory response," Dr Taylor comments. "They also seem to affect worm fertility. The larvae don’t develop and embryo viability drops. This means that Wolbachia has emerged as the only target for chemotherapy that results in the long-term sterility of the worms in human hosts."

These results also suggest that, far from being an unwelcome guest in nematodes, Wolbachia actually aids its host. Indeed, Dr Taylor's research showed up yet another Wolbachia trick. "We have indirect evidence that bacterial enzymes may help the nematode evade the host's immune system. Without Wolbachia, worms die within 12 months. With them, an adult worm can live for 5-20 years, spewing out maybe 10 000 worms a day." His group is currently attempting to identify the specific mechanisms underlying this immune evasion.

So, with simple antibiotics, it may now be possible not only to combat the worst effects of filarial disease, but also to increase the time that people are free of it. "Wolbachia has turned the field around," says Dr Taylor. "What is astonishing is the speed at which this is happening - from experiments on a culture plate to redefining the clinical pathology. We're rewriting the book on filariasis, because of this organism."

Genome sequence

In a hunt for the genetic basis of Wolbachia's extraordinary effects on its hosts, both Dr Sinkins and Dr Taylor are collaborating with groups in the UK, Europe, Australia and the Wellcome Trust Sanger Institute to sequence the genomes of their Wolbachia strains. Further sequencing on three other strains, in different hosts, is going on in Europe and the USA.

Comparisons across strains, and in very different hosts, will allow researchers to pinpoint the genes involved in common pathways and in specific host-parasite reactions. For Dr Sinkins, the long-term aim is to understand the mechanisms that drive cytoplasmic incompatibility, because of its importance in controlling insects of medical importance. Dr Taylor sees the possibility of identifying targets for the development of new drugs to treat filariasis. And both scientists simply want to learn what underpins the molecular wizardry of this deceptively simple organism.

External links

• Sequencing the genomes of the Wolbachia: strains in part at the Wellcome Trust Sanger Institute

Further reading

Sinkins S P, O'Neill S L (2000) Wolbachia as a vehicle to modify insect populations. In 'Insect Transgenesis: Methods and Applications' (Ed. Handler A M and James A A) pp 271-288. CRC Press.

Alphey L, Beard C B, Billingsley P, Coetzee M, Crisanti A, Curtis C, Eggleston P, Godfray C, Hemingway J, Jacobs-Lorena M, James A A, Kafatos F C, Mukwaya L G, Paton M, Powell J R, Schneider W, Scott T W, Sina B, Sinden R, Sinkins S, Spielman A, Toure Y, Collins F H (2002) Malaria control with genetically manipulated insect vectors. Science 298: 119-121

Taylor M J, Hoerauf A (2001) A new approach to the treatment of filariasis. Curr. Opin. Infect. Dis., 14(6): 727-31.

Keiser P B, Reynolds S M, Awadzi K, Ottesen E A, Taylor M J, Nutman T B (2002) Bacterial endosymbionts of Onchocerca volvulus in the pathogenesis of post treatment reactions. J. Infect Dis., 185(6): 805-11.

Saint Andre A, Blackwell N M, Hall L R, Hoerauf A, Brattig N W, Volkmann L, Taylor M J, Ford L, Hise A G, Lass J H, Diaconu E, Pearlman E (2002) The role of endosymbiotic Wolbachia bacteria in the pathogenesis of River blindness. Science, 295(5561):1892-5.

Cross H F, Haarbrink M, Egerton G, Yazdanbakhsh M, Taylor M J (2001) Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood. Lancet, 358(9296):1873-5.

Taylor M J, Cross H F, Bilo K (2000) Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J. Exp. Med., 191(8): 1429-36.

Taylor M J, Hoerauf A (1999) Wolbachia bacteria of filarial nematodes. Parasitol. Today, 15(11): 437-42.