How a tiny bacterium is protecting the world from dengue

29 aug 2022

Mosquitoes are the deadliest animal in the world. This is because a simple bite can transmit viruses and parasites that cause diseases such as dengue, Zika, yellow fever, and chikungunya, threatening the health of 4 billion people in the world.

Dengue alone infects up to 400 million people every year, a number that has been dramatically increasing in the last decades. There are several strategies to prevent this and other mosquito-borne diseases, including getting rid of mosquitoes’ egg-laying sites, applying insecticides, and, more recently, a tiny bacterium called Wolbachia.


An accidental discovery

Wolbachia is a bacterium that is naturally present in more than half of insect species, including butterflies and bees. Despite having been described for the first time in 1924, its antiviral effects were discovered just a little over a decade ago. Luís Teixeira, principal investigator at the Instituto Gulbenkian de Ciência (IGC), was one of the first to make this revolutionizing discovery.    

It was precisely at the IGC that his scientific career took off. Here, he began the doctoral programme that would end up boosting his international experience, from Germany, at the European Molecular Biology Laboratory (EMBL), to England. At the end of his first year as a post-doc, at the University of Cambridge, Luís was studying genes involved in viral resistance in fruit flies when he found something unexpected. Despite having the same genetic background, “some flies were more resistant to viruses than others”, he recalls. He was starting to feel really frustrated with this hiccup in his experiments, for which he did not have a good explanation when he remembered an important detail: the flies that were less resistant to viral infection had been treated with an antibiotic. It was then that he realized the antibiotic was getting rid of an important line of defense for the flies, the Wolbachia bacterium.

These results, in parallel with those obtained from a research team at the University of Queensland, also in the year 2008, were enough to completely transform the way we fight mosquito-borne viral diseases nowadays.


Wolbachia to the rescue

As soon as they found out about the protective effects of Wolbachia, scientists started wondering how this advantageous feature could be exploited to stop the transmission of diseases by insects. “As soon as I realized it was Wolbachia that was giving antiviral protection, I immediately thought of its application in mosquitoes”, Luís Teixeira recalls. If introducing this bacterium into mosquitoes made them more resistant to viruses, similarly to what happened in fruit flies, these would be less likely to transmit viral diseases to humans.

It didn’t take long for this to happen. In 2011, the World Mosquito Program released the first mosquitoes with Wolbachia in Australia. Since then, these modified mosquitoes have been released in a total of twelve countries in Asia, Latin America, and Oceania to stop the spread of dengue. Wolbachia is transmitted from one generation of insects to the next and has mechanisms to spread and be maintained in the population. This makes this new strategy self-sustaining and safe, contrarily to previous efforts to control dengue, such as the use of insecticides, which were not proven effective in the long run.

It’s a long way from the lab to the field, but the results that are starting to emerge are very promising. Proof of this is the city of Yogyakarta, in Indonesia, which is frequently affected by large outbreaks of dengue. A report published last year reveals that, after releasing mosquitoes with Wolbachia in this region, the number of new cases of dengue has decreased by 77% and hospitalizations by 86%. But the usefulness of this strategy goes beyond this. In Brazil, chikungunya cases have dropped in a similarly surprising way.


The science of superpowers

Wolbachia is, without a doubt, saving many lives, but we still don’t know how its superpowers work. We know that when fruit flies have this bacterium, viruses either cannot infect them or they do it at very low levels. “But we do not know exactly how Wolbachia does that, how it interferes with the infection”, Luís explains. We know very little about how Wolbachia interacts with insects at the molecular level, how it can live inside their cells, what it needs from them, how it manipulates them, and how it controls its own proliferation and levels. Knowing this would be very important because we still don’t know very well how this system is going to evolve outside of the lab”, he adds.

The first field results are, indeed, promising. Ten years have passed since these mosquitoes have been released and Wolbachia levels remain high. But the truth is that we don’t know if this method will be enough to eradicate these diseases or if the responsible viruses will evolve to escape the protection this bacterium provides. This is why researchers keep thinking about how this strategy can be improved. But for that, they first need to fully understand how Wolbachia does what it does.

This is the focus of IGC’s research group led by Luís Teixeira, which studies how fruit flies interact with microbes. It might not seem like it, given its small size, but the immune responses of fruit flies are, to some extent, similar to those of mammals. For that reason, and because they are easy to maintain in large numbers, these are frequently used to elucidate defense mechanisms against infectious agents. But their genetic resemblance to humans is not the only thing that makes them valuable. By recurring to this model, scientists can study how insects in general interact with microbes, be that viruses or bacteria, which is of great interest to us given their role in transmitting diseases, in agriculture, and in maintaining the balance in ecosystems.

With their most recent project, funded by the European Research Council (ERC), the group has been unraveling fundamental aspects of Wolbachia and its antiviral effect. In one of their studies, the group identified important alterations in the bacteria’s genetic information that increase their proliferative capacity. It is known that the higher the titers of this bacterium in the host, the higher its resistance to viruses. But this comes with a cost to the insect: its lifespan decreases. Consequently, bacteria cannot be transmitted to the next generation, being quickly eliminated. The same has been observed in nature: when mosquitoes carrying a highly proliferating Wolbachia variant were released in Vietnam, these failed to protect the communities, because they died before transmitting the bacteria to their offspring. This is why the mosquitoes that are now being released have Wolbachia that proliferate a little less”, Luís clarifies.

But the growth of the bacteria is not the only factor determining its antiviral effect: the conditions inside the insect hosts are another aspect to consider. “We found in the lab that if the flies develop at a relatively low temperature, then Wolbachia is still there but there is no protection whatsoever”, Luís explains. “The temperature of development determines the degree of protection”, he concludes. This could have consequences: in colder regions, this bacterium could end up not preventing the transmission of viruses by mosquitoes, despite being present in populations.

As we can see, interactions with microbes are not as simple as they might seem and the success of this recent strategy to stop the spread of viral diseases depends on a lot of factors, many of which we probably still don’t know. To explore all this complexity, science needs multidisciplinary teams and a lot of collaboration. “Crossing research fields and collaborating with people with different expertise is always important because there are always many approaches to tackle these problems and questions we are trying to solve”, says Luís Teixeira. The researcher knows what he is talking about since he leads the SymbNET project, which brings together top European institutions in the study of host-microbe symbiotic interactions. The goals of the project are exactly those: to promote interaction between people with different know-how and expertise, collaboration, and learning. “It is always good to collaborate with people who have other perspectives, who ask other questions and use other techniques”, he adds. Maybe that is the key to deciphering how Wolbachia’s superpowers work and how these can be explored to prevent not only dengue but eventually other mosquito-borne diseases that are threatening more and more communities around the world.

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