The Fight Against Malaria Is A Race Against Resistance

Nothing has done more to fight the spread of malaria in Africa than bed nets laced with pesticides, according to a recent public health study (Nature 2015, DOI: 10.1038/nature15535).

Researchers and public health officials started distributing these nets to malaria-plagued nations about 15 years ago, providing a strong defense against the mosquitoes that were spreading the disease. But this defense is static, and mosquitoes evolve.

Of the 65 countries that have monitoring programs, 53 have found mosquitoes that have become resistant to at least one pesticide since 2010, according to a report from the World Health Organization (WHO).

An international research team led by biologist Marit Farenhorst has now developed an approach that capitalizes on chemistry and mosquito behavior to render existing pesticides lethal once more. Still, the researchers—and scientists worldwide—recognize that this alone will not stop the spread of resistance or mosquito-borne illnesses.

“For mosquito control, you’ve got to use everything you’ve got,” says Farenhorst, who works for the Dutch company In2Care, which develops products to help keep disease vectors, such as mosquitoes, in check.

The team’s new addition to the mosquito control arsenal is a pesticide-treated netting that differs from bed nets in a key way. Bed nets are typically infused with pesticide; the new nets are coated in it (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1510801112)

Bed net manufacturers impregnate the fibers of their protective meshes with pyrethroid pesticides, such as deltamethrin. This infusion minimizes human exposure, allowing people to safely handle the nets because pyrethroids are nonhazardous to humans at low doses. Unfortunately, the same is becoming increasingly true of mosquitoes.

Farenhorst’s team introduced a net that exposes mosquitoes to higher lethal doses of pesticide by coating the exterior of commercial polyester nets with insecticide powders. With this approach, the team found it could kill mosquitoes with the same pesticides the insects had become resistant to.

The netting, developed by the Dutch company Van Heek Textiles to trap airborne pollen, is designed to cling to electrically charged pesticide powders. The net holds the pesticide in place until a mosquito lands on it, Farenhorst says.

“You get really good transfer of the insecticide to the mosquito,” Farenhorst tells C&EN. “The mosquito gets a high dose, even though it’s usually only the tips of its little legs that touch the net.”

The netting itself is charged thanks to a special, nonhazardous chemical coating, says Harold Meijnen, a Van Heek international sales manager. He’s not revealing what that chemical is, but he says that the coating’s polarizability enables it to develop a positive charge that clings to the negatively charged pesticides.

“I suspect the coating is particularly good at building up static charge—like when you shuffle your rubber-soled shoes against the carpet,” explains Marc A. Hillmyer, director of the Center for Sustainable Polymers at the University of Minnesota. Hillmyer, who was not involved in the study, adds that a silicone or fluorinated coating could allow for the easy accumulation of charge. “Not sure if that is exactly what’s going on, but it’s one possibility.”

The In2Care team reports that its nets kill six different pyrethroid-resistant mosquito strains far better than bed nets. Farenhorst and her colleagues have deployed the nets in 1,800 homes in Tanzania and have observed more than a 90% reduction in mosquitoes in these dwellings, she tells C&EN.

Because the mesh is coated with pesticide, however, people can’t routinely wash or handle the new nets. So the researchers have encased their nets within plastic tubes, creating simple pipe-like traps. They can then install these traps in the eaves of homes—the gaps between a dwelling’s walls and roof that mosquitoes fly through. These eaves tubes can thus be used in combination with bed nets for enhanced protection, Farenhorst says.

“I think that what they’re doing is excellent and very important,” says Luisa Nardini, a mosquito genetics researcher at the Pasteur Institute, in Paris, who was not involved with the In2Care project.

Still, the new nettings rely on existing pesticides. And many different mosquito populations exhibit resistance to at least one of the four classes of insecticide approved by WHO, Nardini says.

When it comes to pyrethroids, mosquitoes have evolved two primary defense strategies. Some mosquitoes can upregulate the production of enzymes, such as monooxygenases, that detoxify the pesticide, Nardini says. Other bugs have acquired mutations in the protein receptors that bind pyrethroids, rendering the protein ineffective.

Even at elevated doses, pyrethroids would be largely ineffective against mosquitoes with the latter defense. Similarly staunch resistance mechanisms will or have emerged in response to other existing pesticides, which means those compounds’ days are numbered. But those are the only options available now, Nardini says. “We have a problem now and people need help now. It’s far from an ideal situation.”

Protecting developing nations against malaria will take new strategies using existing chemicals, but also brand-new pesticides, she tells C&EN. Because of evolution, researchers must keep themselves from falling in love with the next big strategy that works as well as pyrethroid bed nets once did, says Andrew F. Read, who is also not involved with the In2Care effort.

Six years ago, Read, a professor of entomology and biotechnology at Pennsylvania State University, helped write a manuscript with an unusually bold and provocative title: “How To Make Evolution-Proof Insecticides for Malaria Control” (PLOS Biol. 2009, DOI: 10.1371/journal.pbio.1000058). The paper faced criticism from some researchers, and one reviewer said that pesticide resistance simply wasn’t a problem, Read recalls.

“It’s a repeated story. We find a fabulous silver bullet, and everyone gets excited,” he says. For malaria control, that silver bullet appeared to be pyrethroid-impregnated bed nets. People thought they had solved the mosquito problem.

“But then evolution comes along,” Read says. “It’s almost like we don’t understand evolution happens.”

Now, insecticide resistance is the single biggest threat to undoing the victory won by bed nets. Read is still advocating the approaches he called for six years ago: using existing pesticides in combinations, developing new synthetic pesticides, and exploring natural alternatives, like mosquito-killing fungi.

And any solution must be rolled out intelligently, Read says. History has shown that reckless use of pesticides accelerates the development of resistance. Read commends the recent In2Care project as a step in the right direction.

“I don’t think there’s going to be a magic bullet,” he says. “We’re going to need lots of approaches, and this one is exciting.”

In2Care has already started working with a fungal biopesticide that Read wrote about in 2009. Farenhorst and her colleagues have also loaded their electrostatic nets with a slow-acting fungus—Beauveria bassiana—and a larvicide to fight the spread of the dengue virus.

These nets targeting dengue vectors use a different route of attack compared with the ones battling insects carrying malaria. The antimalaria eaves tubes are designed to kill mosquitoes of the genus Anopheles within minutes of the insects touching the pyrethroid-coated nets. These bugs are looking to feed, and nets need to kill them quickly to stop the spread of the malarial parasite.

But the fight against dengue is different. Public health officials need to stop Aedes mosquitoes from breeding, Farenhorst says. In2Care’s dengue traps expose a mother mosquito to fungal spores that will kill her after she lays eggs. But, in addition to the eggs, she also deposits the larvicide that will then kill her offspring as well as other larvae growing in the same pool of stagnant water.

In2Care has already deployed its dengue traps in 14 countries, primarily in the Caribbean, Farenhorst tells C&EN.

The team’s electrostatic coating approach is flexible, and that allows it to be maximally effective, she says. It can be extended to a number of net materials, which can be coated with a variety of pesticides to exploit a mosquito’s behavior to best kill it, she adds.

“It’s designed to be very effective because it needs to be very effective.”