After bed nets, insecticides and sterile and genetically modified insects, scientists are now adding a genetically engineered toxic fungus to the arsenal of weapons that could be used to wipe out mosquitoes that carry the malaria parasite.

Although insecticides and insecticide-laced bed nets – by far the two most commonly employed strategies – have effectively lowered the numbers of infections and deaths, the global malaria burden has failed to decline . In 2017, 219 million people were infected with malaria and an estimated 435,000 died. That is because mosquitoes are evolving resistance to insecticides.

The rapid evolution of resistance is a common and recurrent theme in our arms races against malaria-transmitting mosquitoes, as well as against pests and pathogens in general. Over time, organisms mutate and evolve resistance to any new drug that is used to kill them. No wonder humans always end up on the losing side. This is why a new weapon is needed. And the latest one is a killer fungus.

Research on kinds of mosquitos and how they can be exterminated has been underway for several years. Credit: US Air Force
Research on kinds of mosquitos and how they can be exterminated has been underway for several years. Credit: US Air Force

Fighting killers with killers

As an evolutionary biologist studying fungi, I am familiar with the ability of these organisms to cause devastating diseases in diverse plants and animals, including humans. While many fungal pathogens infect a broad range of hosts, some attack only a select few.

This realisation led scientists to a new strategy to fight malaria – infect and kill disease-transmitting mosquitoes using fungal pathogens that they normally encounter in nature. This isn’t the first time that fungi have been weaponised. In fact, this is precisely the strategy behind the highly successful biological pesticide, Green Muscle, which kills locusts and grasshoppers.

Infecting mosquitoes with their natural pathogens – such as the pathogenic fungi from the genus Metarhizium – is a particularly attractive strategy because, unlike bacterial or viral pathogens, fungi can infect mosquitoes simply by coming into contact with them and don’t have to be ingested. Also, fungi are generally friendlier to the environment than traditional chemical insecticides.

Does this work?

Fifteen years ago, a field trial in rural Tanzania showed that it could. Hanging cotton sheets inoculated with insect-killing fungi on the ceilings of houses where mosquitoes rest, researchers observed that one-third of the mosquitoes in the region were infected. According to malaria transmission models, such an infection rate could reduce malaria cases by 75%.

However, the Tanzanian field trial showed that the Metarhizium fungi is not always capable of infecting their mosquito hosts. Besides, fungal infections typically take several days to kill mosquitoes. In the lab, for example, fungi take an average of between seven and nine days to kill mosquitoes, depending on the dosage.

Brian Lovett, a graduate student working at Ray St. Leger’s lab, and Etienne Bilgo, a post-doctoral fellow working with entomologist Abdoulaye Diabate found a solution.

Lovett and Bilgo found that they could use a fungus that had been genetically modified to produce a toxin called “Hybrid”. This toxin specifically attacks the nervous system of arthropods, the animal group that includes insects and their kin, like spiders and crustaceans. Laboratory experiments in 2017 by the same team had already shown that these genetically modified fungi kill mosquitoes quicker than unmodified ones.

The big question now was whether this strategy would work in nature.

The MosquitoSphere team in Soumousso, Burkina Faso. Credit: Brian Lovett/The Conversation
The MosquitoSphere team in Soumousso, Burkina Faso. Credit: Brian Lovett/The Conversation

The ‘MonsquitoSphere’

To reduce the risks posed by field testing, Lovett and Bilgo tested their GM fungus in the “MosquitoSphere”, a large, screened-in field specially designed to closely match outdoor conditions in Soumousso, Burkina Faso. By setting up huts with cotton sheets that contained spores of genetically modified toxin-producing Metarhizium fungi as well as ones with spores of unmodified fungi (as controls), Lovett and Bilgo found that up to 80% mosquitoes were infected in both huts. The difference was that mosquitoes in huts with genetically modified fungi died within an average of five days whereas mosquitoes in huts with unmodified fungi died after close to nine days.

The MosquitoSphere huts in Soumousso, Burkina Faso, where genetically modified killer toxic fungi was used. Credit: Brian Lovett/The Conversation
The MosquitoSphere huts in Soumousso, Burkina Faso, where genetically modified killer toxic fungi was used. Credit: Brian Lovett/The Conversation

By examining how mosquito populations fared over time, the researchers also discovered that genetically modified fungi infected multiple generations of mosquitoes. For example, in one enclosure of genetically modified fungi, an initial population of 1,500 mosquitoes, collapsed to just 13 after a month and a half.

Thus, by genetically arming an already deadly fungal pathogen with a powerful toxin, the investigators were able to dramatically reduce the mosquito “field” population in a part of the world where malaria is endemic and mosquitoes are resistant to chemical insecticides.

Promises and risks

Today, there is an urgent need to curb malaria transmission, particularly in sub-Saharan Africa, where 92% of the world’s cases and 93% of global deaths occur. The US Environmental Protection Agency’s approval of the hybrid toxin under the commercial name Versitude, and the approval of the use of unmodified Metarhizium fungi as a “biopesticide” by several African countries may pave the way to green-light the use of genetically modified Metarhizium fungi in the fight against malaria.

On the flip side, releasing fungi carrying a deadly insect toxin raises concerns about unintentional harm to “nontarget” insects. Metarhizium fungi infect only a small range of insects and experiments where nontarget insects such as honeybees, were infected by both the genetically modified and unmodified fungi, did not affect their survival. Further, even if the gene found its way into fungi that infect humans – a highly unlikely scenario – it would not have any effects on us because the toxin only works on insects.

However, restricting the spread of the gene that produces the hybrid toxin in organisms other than Metarhizium fungi is a potential concern. One safety precaution could be to add genetic switches that reduce survival of the fungus outside the indoor environment. Already various inherent features of the Metarhizium fungi – such as their large, non-airborne and sensitive-to-ultraviolet-light spores – reduce their chances of dispersal.

To conclude, while promising, this strategy of essentially poisoning mosquitoes with genetically engineered fungi is not guaranteed. Mosquitoes could evolve resistance to this. But with hundreds of thousands of people dying each year because of these pathogens, like our opponents, we’ll need to keep evolving our strategies as well.

Antonis Rokas is the Cornelius Vanderbilt Chair in Biological Sciences and a professor at the Vanderbilt University.

This article first appeared in The Conversation.