CYP-mediated permethrin resistance in Aedes aegypti and evidence for trans-regulation.

Letícia B Smith,Rakshit Tyagi,Shinji Kasai,Shinji Kasai,Jeffrey G Scott,Geraldine Marie Foster

doi:10.1371/journal.pntd.0006933

Letícia B Smith, Rakshit Tyagi + Show 4 more

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https://doi.org/10.1371/journal.pntd.0006933

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Abstract

Aedes aegypti poses a serious risk to human health due to its wide global distribution, high vector competence for several arboviruses, frequent human biting, and ability to thrive in urban environments. Pyrethroid insecticides remain the primary means of controlling adult A. aegypti populations during disease outbreaks. As a result of decades of use, pyrethroid resistance is a global problem. Cytochrome P450 monooxygenase (CYP)-mediated detoxification is one of the primary mechanisms of pyrethroid resistance. However, the specific CYP(s) responsible for resistance have not been unequivocally determined. We introgressed the resistance alleles from the resistant A. aegypti strain, Singapore (SP), into the genetic background of the susceptible ROCK strain. The resulting strain (CKR) was congenic to ROCK. Our primary goal was to determine which CYPs in SP are linked to resistance. To do this, we first determined which CYPs overexpressed in SP are also overexpressed in CKR, with the assumption that only the CYPs linked to resistance will be overexpressed in CKR relative to ROCK. Next, we determined whether any of the overexpressed CYPs were genetically linked to resistance (cis-regulated) or not (trans-regulated). We found that CYP6BB2, CYP6Z8, CYP9M5 and CYP9M6 were overexpressed in SP as well as in CKR. Based on the genomic sequences and polymorphisms of five single copy CYPs (CYP4C50, 6BB2, 6F2, 6F3 and 6Z8) in each strain, none of these genes were linked to resistance, except for CYP6BB2, which was partially linked to the resistance locus. Hence, overexpression of these four CYPs is due to a trans-regulatory factor(s). Knowledge on the specific CYPs and their regulators involved in resistance is critical for resistance management strategies because it aids in the development of new control chemicals, provides information on potential environmental modulators of resistance, and allows for the detection of resistance markers before resistance becomes fixed in the population.

Highlights

Aedes aegypti is an important pest capable of transmitting four important human disease viruses: dengue, yellow fever, chikungunya, and Zika
Given that A. aegypti has a wide global distribution, high vector competence for several arboviruses, frequently bites humans and thrives in urban environments, it poses a serious risk to human health
The 3-fold difference in the resistance ratio (RR) between the CKR and SP strains suggests some minor mechanism of resistance was lost during the isolation of the CKR strain

Summary

Introduction

Aedes aegypti is an important pest capable of transmitting four important human disease viruses: dengue, yellow fever, chikungunya, and Zika. For example, causes morbidity and mortality in 141 countries across the tropical and subtropical regions of the world and is estimated to be a risk to over 50% of the world’s population [1]. Yellow fever is an endemic disease in the tropical regions of Africa and South America with a recently rising number of cases in Brazil [2,3]. Chikungunya is a disease new to the Americas as of 2013 [4] that often causes debilitating joint pains in addition to flu-like symptoms. Given that A. aegypti has a wide global distribution, high vector competence for several arboviruses, frequently bites humans and thrives in urban environments, it poses a serious risk to human health

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