x Abu Dhabi, UAEWednesday 24 January 2018

Infecting them before they infect us

Mosquitoes that transmit dengue fever are old enough to have incubated the virus sufficiently to cause an infection. So by shortening the life spans of mosquitoes, scientists hope to curb dengue fever and a number of other mosquito-borne maladies.

Jessica Abreu da Silva, 6, was hospitalised after being diagnosed with dengue fever in Rio de Janeiro. The city has responded to its mosquito problem by spraying insecticide and poisoning standing puddles of water.
Jessica Abreu da Silva, 6, was hospitalised after being diagnosed with dengue fever in Rio de Janeiro. The city has responded to its mosquito problem by spraying insecticide and poisoning standing puddles of water.

The patient is terminal, its body racked by a parasite that is concentrated in the brain, nervous system, and reproductive tissues. Eventually the parasitic bacteria mushrooms inside the host's cells, resembling "a bag of popcorn in the microwave", and the victim dies. It sounds like a fairly nasty bug, but, then again, its victim is a mosquito. Scientists at 10 educational and research institutes have been working to inject a strain of the parasite, the Wolbachia bacteria, into mosquitoes to shorten their lifespan and protect humans from the diseases they transmit. The study group published its first successful results in the journal Science earlier this month.

The latest research relates to dengue fever, but there is hope that it will lead to the alleviation of a host of mosquito-borne diseases including Japanese encephalitis, West Nile virus, lymphatic filoriasis, elephantiasis, African sleeping sickness, river blindness and malaria, the biggest killer of them all. Dengue - one of the most common mosquito-borne infections but less dangerous than malaria - was chosen not because of the nature of the disease but because of its mode of transmission. The primary vector is the Aedes aegypti mosquito, which feeds almost exclusively on human blood. Also, the tiny predators are easy to breed in the lab.

Because a mosquito has to pick up dengue from an infected human, incubate the virus until it reproduces enough to form a reservoir and then bite other humans, older insects generally spread the disease. "Once it gets quite old if it's lucky enough to live that long, it can keep on infecting many people, that one mosquito, because it is taking meals every day," said Prof Scott O'Neill of Australia's University of Queensland, the lead investigator of the project. "What we have with dengue is quite a small number of mosquitoes, and those mosquitoes are probably very, very old, and they're contributing to nearly all the transmission of the virus."

The researchers have found that infecting mosquitoes with Wolbachia bacteria effectively halves the lifespan of the host. But the potential for a systemic solution to disease stems from Wolbachia's effect on natural selection. Infected females pass on the infection to their larvae. Males do not, but if they fertilise the eggs of uninfected females, those eggs will not hatch, "so the Wolbachia-infected sisters of those males get an advantage and they leave behind more offspring, and all of those offspring carry the infection".

"This is the really cool part of the biology of the bacteria. It's able to effectively prevent mosquitoes that are uninfected with it from reproducing," Prof O'Neill said. "It's almost like a spiteful way in which the infection is able to spread by effectively being detrimental to females that don't have it." Wolbachia is a common parasite in nature, with various strains infecting at least 20 per cent of insect species by conservative estimates. The popcorn metaphor for pathogenicity comes from the work of Dr Seymour Benzer, a former biologist at California Institute of Technology famous in scientific circles for naming the pathogenic strain of the bacteria after popcorn.

"He looked in sections of brain tissue, these bacteria kept on dividing and replicating, and they mimicked bags of microwave popcorn expanding full of bacteria," Prof O'Neill said. "Because the nerve cells are not dividing themselves, and similarly with muscle tissue, the infection builds up in those tissues. It's dividing the bacteria when it probably shouldn't be, and over time that causes the death of the insect. That's why only the mature insects end up dying."

The studies of Wolbachia in southern California fruit flies, where the infection rate is approximately 99.8 per cent in the insect population, are the acknowledged progenitors of the current work. The trick with mosquitoes was to transfer the parasite from its natural hosts to Aedes aegypti - Prof O'Neill said 10,000 mosquito embryos less than 30 minutes old had been injected with Wolbachia, a process that took 18 months.

Because of Aedes aegypti's refined palate and the delicacy of the experiment, human volunteers were used to feed the test subjects under controlled conditions. Only two of the five lines of infected insects survived to form viable populations, a failure rate that Prof O'Neill ascribed to the difficulty of the initial in vitro infections. Once a population is established and released into the environment, mathematical models predict infection rates exceeding that found in fruit flies.

There is a raft of concerns about tampering with nature by introducing a parasite into a new population. The research is accompanied by ancillary social science studies gauging public perceptions of the project which have focused on the effect on the overall ecosystem and the possibility of a species jump in particular. According to Prof O'Neill, in the case of Aedes aegypti, the "cockroach" of the mosquito world, some concerns are minimalised because its habitat is situated near its prey - in other words, in people's homes or the immediate vicinity, which is not a particularly pristine ecosystem.

In terms of species jump, he points out the difficulty his colleagues had infecting mosquitoes in the first place. "We worked really hard for a long period of time to get this into mosquitoes and had to do a whole lot of tricks in the lab to make it happen, so our natural feeling is that it is not just going to pop into a honeybee or something else very easily in the field. Actually, people who work with these bacteria and understand the evolutionary biology all agree that it is very restricted. It jumps over evolutionary time scales very rarely to a new, closely related species, but over the biological timeframes we are talking about doing some sort of controlled intervention, we see that as very unlikely."

Resolving these concerns will in part determine the future of the project. The study group is now embarked on a larger experiment in outdoor field cages in Queensland, Austrailia to test the mathematical models of infection rates outside of controlled laboratory conditions. (The food source will be blood bank stock heated underneath artificial skin). That project starts in February and should take 18 months.

"If those experiments are good, then we will do an actual open release, hopefully if we have regulatory approval, within Australia, within two to two and half years," Prof O'Neill said. That open release could be conducted on an island or similarly isolated locale, and would primarily be intended as another trial run. Then, if all goes according to plan, the theory would be put into practice, and mosquitoes in disease centres such as Vietnam or Thailand could be going popcorn within the next five years.