Abstract
Metabolic resistance threatens the sustainability of pyrethroid-based malaria control interventions. Elucidating the fitness cost and potential reversal of metabolic resistance is crucial to design suitable resistance management strategies. Here, we deciphered the fitness cost associated with the CYP6P9a (P450-mediated metabolic resistance) in the major African malaria vector Anopheles funestus. Reciprocal crosses were performed between a pyrethroid susceptible (FANG) and resistant (FUMOZ-R) laboratory strains and the hybrid strains showed intermediate resistance. Genotyping the CYP6P9a-R resistance allele in oviposited females revealed that CYP6P9a negatively impacts the fecundity as homozygote susceptible mosquitoes (CYP6P9a-SS) lay more eggs than heterozygote (OR = 2.04: P = 0.01) and homozygote resistant mosquitoes. CYP6P9a also imposes a significant fitness cost on the larval development as homozygote resistant larvae (CYP6P9a-RR) developed significantly slower than heterozygote and homozygote susceptible mosquitoes (χ2 = 11.2; P = 0.0008). This fitness cost was further supported by the late pupation of homozygote resistant than susceptible mosquitoes (OR = 2.50; P < 0.01). However, CYP6P9a does not impact the longevity as no difference was observed in the life span of mosquitoes with different genotypes (χ2 = 1.6; P = 0.9). In this hybrid strain, a significant decrease of the resistant CYP6P9a-RR genotype was observed after ten generations (χ2 = 6.6; P = 0.01) suggesting a reversal of P450-based resistance in the absence of selection. This study shows that the P450-mediated metabolic resistance imposes a high fitness cost in malaria vectors supporting that a resistance management strategy based on rotation could help mitigate the impact of such resistance.
Highlights
Associate editor: Gerald HeckelThe original version of this article was revised due to a retrospective Open Access order
Genotyping of the dead mosquitoes after 30-min exposure and the alive after 90-min exposure to these insecticides as previously described showed that the ability of homozygotes resistant mosquitoes to survive after exposition was higher compared with the homozygous susceptible (SS) as recently described (Weedall et al 2019)
In this study, using the recently designed diagnostic assay for CYP6P9a gene, we investigated the fitness cost associated with P450-based resistance on various life traits of malaria vectors using laboratory strains of An. funestus revealing a significant cost imposed by P450-mediated resistance
Summary
Reciprocal crosses were performed in January 2017 between FANG and FUMOZ-R, two An. funestus laboratory strains for several generations in order to bring the CYP6P9a resistance into a susceptible genetic background. FUMOZ-R is a pyrethroid (permethrin) resistant selected strain originates from southern Mozambique (FUMOZ-R) (Hunt et al 2005) and kept in colony since July 2001. This strain was selected based on its resistance status after 1 h exposure to permethrin after WHO bioassays (WHO 1998) and currently exhibits 0% mortality at 0.75% permethrin exposure. The FANG strain originates from southern Angola and kept in colony since January 2003 and is fully susceptible to all major vector control insecticides. Pupae of each strain were collected and put individually in 15 ml falcon tubes for individual emergence the males of the resistant strain were mixed into a same cage with the females of the susceptible colony (and reciprocally) for random mating to generate the first generation
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