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Insecticide Resistance Marker in Malaria Vector Tracks With Reduced Efficacy of Treated Bednets

NEW YORK (GenomeWeb) – A team of researchers from the UK, Cameroon, and Benin has tracked down genetic markers for pyrethroid insecticide resistance in the mosquito Anopheles funestus, the major vector for malaria parasites in Africa, leading to a DNA-based test for a resistance allele that is common to mosquitoes in southern Africa.

In a field study, they used the test to show that bednets treated with pyrethroid were less effective against mosquitoes carrying the resistance allele.

"We detected key DNA-based markers of pyrethroid resistance and designed a field-applicable diagnostic assay," senior author Charles Wondji, a researcher affiliated with the Liverpool School of Tropical Medicine and infectious disease research centers in Cameroon, and his colleagues wrote in a paper published in Science Translational Medicine today.

The researchers sequenced the transcriptome of mosquitoes collected in southern, Eastern, Western, and Central Africa — data complemented by whole-genome sequencing on mosquito samples from southern Africa. Their findings revealed varying levels of insecticide resistance gene expression from one African locale to the next and uncovered structural variants, transcription factor binding site changes, and other alterations that appear to be under selection in Africa as insecticide-treated bed nets became more widely used.

Based on these findings, the team went on to establish a DNA-based assay focused on a cytochrome P450 allele that is linked to pyrethroid resistance in A. funestus mosquito populations from southern African sites sampled in Malawi.

"We used this assay to track pyrethroid resistance across Africa and to demonstrate that this metabolic resistance in mosquitoes reduced the efficacy of insecticide-treated bednets for preventing malaria transmission," the authors wrote.

Insecticide-treated bednets significantly dialed down malaria rates, the team explained, but there are concerns that the effectiveness of that approach may wane as more and more mosquito vectors for malaria become resistant to pyrethroid and other insecticides, prompting research into the molecular changes that lead to target site-insensitivity or metabolic resistance to insecticides.

"Although candidate resistance genes have been detected, it has proved difficult to dissect the molecular bases of metabolic resistance and to detect associated molecular markers because of the size of gene families involved in detoxification, redundancy among their members, and the multiple mechanisms through which metabolic resistance can arise," the author explained.

To delve into the metabolic side of insecticide resistance in A. funestus mosquitoes, the researchers performed Illumina RNA sequencing on pools of female mosquitoes collected in Malawi, Uganda, Ghana, and Cameroon. By analyzing these data alongside RNA-seq data for lab-grown, insecticide-susceptible A. funestus mosquitoes, they tracked down genes with differential expression within and between the insecticide-resistant A. funestus mosquito populations.

Their analysis uncovered differential gene expression involving genes from pathways involved in iron binding, oxidoreductase enzyme activity, and other processes in mosquitoes from Malawi and Ghana, for example, while A. funestus mosquitoes in Uganda appeared to have higher-than-usual expression in genes in detoxification families.

Along with mutations detected by whole-genome sequencing in southern African mosquitoes with high expression of certain CYP genes, the team also identified a cytochrome P450 allele called CYP6P9a_R that served as the foundation for a restriction fragment length polymorphism PCR (PCR-RFLP)-based DNA test for finding pyrethroid resistance, particularly in Malawi where the CYP6P9a_R allele has almost reached fixation in A. funestus mosquitoes.

"We detected a DNA-based resistance marker for cytochrome P450-mediated metabolic resistance to pyrethroids and designed a field-applicable diagnostic assay to detect and track the spread of insecticide resistance across Africa," the authors reported.

They cautioned that the assay appears to be most adept at detecting pyrethroid resistance in A. funestus mosquitoes from southern Africa and called for further research to unravel insecticide resistance markers in other mosquito species and in other parts of the African continent. Even so, they noted that the current findings "highlight the need to introduce a new generation of insecticide-treated bednets for malaria control that do not rely on pyrethroid insecticides."