Scientists say adding “PBO” to mosquito nets could help contain malaria in some areas

Some mosquitoes that spread malaria are genetically adapting to become resistant to common insecticides. This means they survive the deadly chemicals often embedded in mosquito nets, which puts more people at risk of malaria infection. 

Researchers have now identified some of the genetic mutations that may be driving this adaptation. They say adding another chemical called piperonyl-butoxide (PBO) to mosquito nets could help control at least one species of resistant mosquito. Malaria is a deadly disease carried by some breeds of mosquitoes. One of the most widely used and highly effective malaria prevention tools is a long-lasting net treated with pyrethroid. Pyrethroid is a type of insecticide, which is a substance used to kill insects like mosquitoes. 

Unfortunately many mosquitos have adapted to survive pyrethroid, meaning that these nets are no longer effective to control malaria in certain areas.  

Researchers wanted to know what exactly has changed in the DNA of resistant mosquitoes that allows them to evade pyrethroid. They wanted to identify specific genes behind this new trait of pyrethroid resistance, and how the resistance itself works (its mechanism). In other words, they wanted to determine how the mosquito’s body is able to metabolise, or process, the pyrethroid, since the chemical is usually deadly.

These researchers analysed the genes of Anopheles gambiae mosquitos, which are common in Kenya, Uganda, and other African countries. Once they identified specific genes and mechanisms behind this mosquito’s pyrethroid resistance, they tried adding a different chemical to the nets to see if the mosquitoes would still survive. 

The researchers found three genetic mutations that enable the mosquitoes to survive pyrethroid. They say the mutations might benefit the mosquitoes in other ways too, because they appear to have spread very quickly in the populations that the researchers sampled. It seems that the mutations arose in the Kenya-Uganda border region around Lake Victoria. They also say this triple mutation appears to increase the expression of genes able to metabolise the insecticide, and strongly predicts the ability to resist pyrethroids.

Finally, they determined that adding the chemical piperonyl-butoxide (PBO) to the pyrethroid when treating nets was more effective at overcoming the resistance of these mosquitoes.

Previous studies focused on a few specific genes that scientists thought could be behind insecticide resistance. This study broadened the search by checking through thousands of genes to find new mutations common in resistant mosquitoes. The researchers say it is impossible to know from their study what other effects the mutations they identified may have, or how exactly each mutation affects pyrethroid resistance. They also say other mosquito breeds with the same mutations have an increased resistance to pyrethroid insecticides. However, it is unclear if adding an insecticide like PBO would kill these other resistant breeds too.

Researchers from Kenya, Uganda, Congo, Tanzania, Kilifi, the UK, and the USA collaborated on this study. They focused on mosquitos found along the Kenyan-Ugandan border, and their novel idea of adding PBO to nets could save many African lives.

Abstract

Insecticide resistance provides both an increasingly pressing threat to the control of vector-borne diseases and insights into the remarkable capacity of natural populations to show rapid evolutionary responses to contemporary selection. Malaria control remains heavily dependent on deployment of pyrethroid insecticides, primarily in long lasting insecticidal nets (LLINs), but resistance in the major malaria vectors has increased over the last 15 years in concert with dramatic expansion of LLIN distributions. Identifying genetic mechanisms underlying high-level resistance in mosquitoes, which may almost entirely overcome pyrethroid efficacy, is crucial for the development and deployment of potentially resistance-breaking tools. Using the Anopheles gambiae 1000 genomes (Ag1000g) data we identified a very recent selective sweep in mosquitoes from Uganda which localized to a cluster of cytochrome P450 genes, including some commonly implicated in resistance. Further interrogation revealed a haplotype involving a trio of mutations, a nonsynonymous point mutation in Cyp6p4 (I236M), an upstream insertion of a partial Zanzibar-like transposable element (TE) and a duplication of the Cyp6aa1 gene. The mutations appear to have originated recently in An. gambiae from the Kenya-Uganda border region around Lake Victoria, with stepwise replacement of the double-mutant (Zanzibar-like TE and Cyp6p4-236M) with the triple-mutant haplotype (including Cyp6aa1 duplication), which has spread into the Democratic Republic of Congo and Tanzania. The triple-mutant haplotype is strongly associated with increased expression of genes able to metabolise pyrethroids and is strongly predictive of resistance to pyrethroids most notably deltamethrin, a commonly-used LLIN insecticide. Importantly, there was increased mortality in mosquitoes carrying the triple-mutation when exposed to nets co-treated with the synergist piperonyl butoxide (PBO). Frequencies of the triple-mutant haplotype remain spatially variable within countries, suggesting an effective marker system to guide deployment decisions for limited supplies of PBO-pyrethroid co-treated LLINs across African countries. Duplications of the Cyp6aa1 gene are common in An. gambiae across Africa and, given the enzymes metabolic activity, are likely to be a useful diagnostic for high levels of pyrethroid resistance.

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