Tag: Wolbachia

Target: elimination

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In an earlier post, I outlined WHO’s goal to be free of elephantiasis by 2020. Global elimination efforts currently rely on multiple rounds of mass drug administration, where doses of medicine are given to entire populations on an annual basis. This is preventative treatment (controlling the spread of parasites), and has worked quite well, as we have seen. In the past, the recommended regimen involves a combination of two antibiotics that target the larval stage, diethylcarbamazine and albendazole.

They are capable of clearing almost all microfilariae from the blood, but come with some unfortunate side effects including fever, headache and dizziness. Making matters worse, the adult worms are long-lived. To break the transmission cycle by killing only larvae requires prolonged drug delivery with extensive coverage; hardly ideal in countries where resources are scarce. Instead, drugs that target the adult worms are desperately needed.

I’ve talked about how the worms rely on their bacterial symbionts for survival, making Wolbachia an obvious target in the elimination of elephantiasis: if you stop the bacteria, you also kill the worm. This has been demonstrated with doxycycline, an antibiotic which belongs to the tetracycline family of antibiotics. These work by binding ribosomes, an important cellular factory, thereby stopping the bacteria from making proteins and reproducing.

Ball-and-stick model of the doxycycline molecule, a tetracycline antibiotic.
Image credit: “Doxycycline 3D ball” by Jynto is licensed under CC0 1.0

Crucially, doxycycline is more effective than the combined treatment, and has none of the problematic side effects as it eliminates the adult worms. Through this novel method of targeting the symbiont, treatment reduces the level of Wolbachia to a level where adult female worms became infertile: a safe, macrofilaricidal treatment.

Doxycycline is the best drug treatment we have, but it has two standout problems: it can be harmful to children and pregnant women, and it takes at least four weeks to work. But, since the drug concept has clinical evidence to support it, the idea has taken off. The initiative was granted funding from the Bill & Melinda Gates Foundation, giving rise to the Anti-Wolbachia Consortium, A·WOL. Their headquarters are at the Liverpool School of Tropical Medicine, and you can see the team in the video below, squashing mosquitos:

Infected abroad: Mosquito Bites by AWOL Wolbachia

The real goal here is to find a treatment which clears infection in under a week. To this end, A·WOL has screened over 2 million compounds, an onerous task. They’ve since identified 20,000 candidates, all active against Wolbachia, and ready for further investigation. That’s pretty much where we are today, with people in lab coats wading through a pile of ‘drug-like compounds’ in search of something that meets the criteria.

The worm and the bacterium

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Wolbachia is a group of bacteria, perhaps the most abundant reproductive parasite in the world. I first heard about them in my final year studies: we were talking about how bacteria are able to manipulate the hosts they infect for their own benefit, and how Wolbachia will dictate whether mating between their insect hosts is successful or not. This was first discovered in the 70s, when scientists at UCLA found that the sperm of infected mosquitos killed the female’s eggs. The phenomenon is called cytoplasmic incompatibility because the bacteria reside in the cytoplasm (the material within a cell). This helps the bacteria to spread through a population of insects, advancing at a rate of up to 100km per year.

Cytoplasmic incompatibility in mosquitos.

Indeed, Wolbachia probably rely on their hosts for survival, as you can’t grow them by themselves. They live in symbiosis with an amazing range of insects and other invertebrates. That is to say, they have an intimate and often interdependent relationship with their hosts. They fit into this story because they also live in symbiosis with the filarial worms that cause elephantiasis. They exist within the parasites that infect humans, creating a bizarre Russian doll situation. As a side note, there is fairly recent evidence that Wolbachia rely on a virus inserted within their own genetic code, to bring about the cytoplasmic incompatibility mentioned previously. Four levels of nested interaction make for a pretty intricate system, by anyone’s estimation.

Regardless, the worms themselves rely heavily on Wolbachia: without their symbionts they very quickly become sterile and die. In studies where antibiotics were used to kill the bacteria, filarial embryos were severely deformed, suggesting that the bacteria are essential in the early development of worm offspring.

Transmission electron micrograph of Wolbachia within an insect cell.
Image credit: “Wolbachia” by Ayacop is licensed under CC BY 2.5

They are also needed for proper regulation of apoptosis, a kind of controlled cell death. Without Wolbachia there is a dramatic increase in apoptosis(and sterility), demonstrating that host and symbiont have coevolved so that this particular aspect of regulation is outsourced (with dire consequences if the symbiont is absent). This is both true for cells of the body, and those of the germline (the cells that pass on their genetic material to offspring). In fact, Wolbachia actually live inside the germline cells of their hosts, and have the amazing peculiarity of being transmitted by the host female germline to offspring, like mitochondria are in humans.

Through this process, called vertical transmission, the Wolbachia have become master manipulators of their hosts to make sure they’re passed on to the next generation. The worms depend on Wolbachia in the germline for two reasons: they maintain a level of dormancy, ensuring a steady stream of egg production for many years, and they encourage the cells to proliferate. This is a rare example of developmental symbiosis, but the obvious application of this knowledge is to target the bacteria and kill the worms indirectly, something I will come onto next.