Malaria has long been a problem in Mali. But in 2006, the situation got worse: a malaria-carrying mosquito species named Anopheles coluzzii became increasingly resistant to common insecticides. Scientists searched for an explanation in its genes. Somehow, the species had acquired mutations that were previously only found in another species, Anopheles gambiae — despite the fact that these two species didn't usually mate with each other, and that their hybrids tended to die without producing offspring of their own, the mutations were identical.
"A man-made change to the environment has actually driven hybridization between two species."
Now, researchers think they know how this insecticide resistance developed. As more nets treated with insecticide were used in Mali, the mosquitoes began to develop resistance. Those once-puzzling mutations likely emerged because the nets favored the survival of insecticide-resistant mosquito hybrids, according to a study published today in Proceedings of the National Academy of Sciences.
To find out how these mutations appeared, a group of researchers analyzed the genes of mosquitoes sampled between 2001 and 2012. They found that the variations that appeared in A. coluzzii started to pop up when the species began to interbreed with A. gambiae more often. The increase in interbreeding took place around that same time as the introduction of a health campaign in Mali, in which officials distributed insecticide-treated nets to its citizens. The researchers concluded that the nets may have driven the transfer of mutations between two species. As the hybridization rates increased, the mutations that conveyed resistance became permanently integrated in the A. coluzzii's genome — a change that would made the nets less effective over time.
The hybrids were now better-adapted to the new, insecticide-net-containing environment, explains Gregory Lanzaro, a vector biologist at the University California, Davis, and one of the co-authors of the study. "So a man-made change to the environment — the use of nets — has actually driven hybridization between two species, ultimately leading to an 'improved' mosquito." That's troubling, he explains, because the nets are "one of the major malaria control strategies being used in sub-Saharan Africa."
This study doesn't definitely prove that the mutations emerged because of the increased use of insecticide-treated nets. To do that, the researchers would have to ask that people in some villages forgo the use of the nets — a procedure that would be medically unethical — to see if it makes a difference in the prevalence of the mutation among A. coluzzii. Still, the researchers think they provide strong evidence for the link. There had been hybrids in the past, and they didn't lead to the spread of this mutation. That supports the idea that the mutation didn't provide a survival advantage for A. coluzzii prior to 2006 — or prior to the increase use of treated nets. "In fact," Lanzaro explains, "these hybrids did not survive."
"a window into the sometimes unexpected genetic processes that can erode the effectiveness of insecticides."
Though the research team's evidence for the treated nets as a sole cause of the change isn't conclusive, "the evidence they present is very compelling," says Daniel Neafsey, a malaria researcher at the Broad Institute of MIT and Harvard University who did not participate in the study. Studies like this, he says, are "a window into the sometimes unexpected genetic processes that can erode the effectiveness of insecticides."
The findings shouldn’t cause anyone to stop using nets in areas with high rates of malaria; nets are still widely considered the frontline tool of malaria control. But Lanzaro believes that there's an urgent need for new methods for malaria mosquito vector control. Scientists are exploring the use of bacteria to kill mosquito larvae, Lanzaro says. And "work is underway to use genetic methods to kill or alter mosquitoes.
We need to consider the mechanisms by which insecticide resistance can emerge
Ultimately, however, the study carries a message for the health officials that promote these types of disease vector control methods, Neafsey says. Our malaria interventions are very successful — which was what created the mutants. "They put an enormous evolutionary pressure on mosquito populations," Neafsey says. That pressure was so pronounced that it favored breeding of two species. Which, oddly, means that nets caused a rapid, partial reversal of the evolutionary processes that led the mosquitoes to branch out into two separate species in the first place. For people who want to control insect-transmitted disease, this study should be a warning shot. Just like we already do with antibiotics, public health researchers should consider the possibility of insecticide resistance. Or as Neafsey puts it: "Evolution must be taken into account when controlling infection diseases."