Tchouakui Magellan, Riveron Miranda Jacob, Mugenzi Leon M J, Djonabaye Doumani, Wondji Murielle J, Tchoupo Micareme, Tchapga Williams, Njiokou Flobert, Wondji Charles S
Centre for Research in Infectious Diseases (CRID), P.O. Box 13501, Yaoundé, Cameroon.
Parasitology and Ecology Laboratory, Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon.
Heredity (Edinb). 2020 May;124(5):621-632. doi: 10.1038/s41437-020-0304-1. Epub 2020 Mar 10.
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 (χ = 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 (χ = 1.6; P = 0.9). In this hybrid strain, a significant decrease of the resistant CYP6P9a-RR genotype was observed after ten generations (χ = 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.
代谢抗性威胁着基于拟除虫菊酯的疟疾控制干预措施的可持续性。阐明代谢抗性的适合度代价及潜在的抗性逆转对于设计合适的抗性管理策略至关重要。在此，我们解析了非洲主要疟疾媒介嗜人按蚊中与CYP6P9a（细胞色素P450介导的代谢抗性）相关的适合度代价。在拟除虫菊酯敏感（FANG）和抗性（FUMOZ - R）实验室品系之间进行了正反交，杂交品系表现出中等抗性。对产卵雌蚊中的CYP6P9a - R抗性等位基因进行基因分型发现，CYP6P9a对繁殖力有负面影响，因为纯合子敏感蚊子（CYP6P9a - SS）比杂合子（优势比 = 2.04；P = 0.01）和纯合子抗性蚊子产卵更多。CYP6P9a对幼虫发育也施加了显著的适合度代价，因为纯合子抗性幼虫（CYP6P9a - RR）的发育明显慢于杂合子和纯合子敏感蚊子（χ = 11.2；P = 0.0008）。纯合子抗性蚊子比敏感蚊子化蛹晚这一现象（优势比 = 2.50；P < 0.01）进一步支持了这种适合度代价。然而，CYP6P9a不影响寿命，因为不同基因型蚊子的寿命未观察到差异（χ = 1.6；P = 0.9）。在这个杂交品系中，十代后观察到抗性CYP6P9a - RR基因型显著减少（χ = 6.6；P = 0.01），这表明在没有选择的情况下基于细胞色素P450的抗性发生了逆转。这项研究表明，细胞色素P450介导的代谢抗性在疟疾媒介中施加了很高的适合度代价，支持基于轮换的抗性管理策略有助于减轻这种抗性的影响。
