20-Hydroxyecdysone (20E) signaling as a promising target for the chemical control of malaria vectors

Abstract

With the rapid development and spread of resistance to insecticides among anopheline malaria vectors, the efficacy of current World Health Organization (WHO)-approved insecticides targeting these vectors is under threat. This has led to the development of novel interventions, including improved and enhanced insecticide formulations with new targets or synergists or with added sterilants and/or antimalarials, among others. To date, several studies in mosquitoes have revealed that the 20-hydroxyecdysone (20E) signaling pathway regulates both vector abundance and competence, two parameters that influence malaria transmission. Therefore, insecticides which target 20E signaling (e.g. methoxyfenozide and halofenozide) may be an asset for malaria vector control. While such insecticides are already commercially available for lepidopteran and coleopteran pests, they still need to be approved by the WHO for malaria vector control programs. Until recently, chemicals targeting 20E signaling were considered to be insect growth regulators, and their effect was mostly studied against immature mosquito stages. However, in the last few years, promising results have been obtained by applying methoxyfenozide or halofenozide (two compounds that boost 20E signaling) to Anopheles populations at different phases of their life-cycle. In addition, preliminary studies suggest that methoxyfenozide resistance is unstable, causing the insects substantial fitness costs, thereby potentially circumventing one of the biggest challenges faced by current vector control efforts. In this review, we first describe the 20E signaling pathway in mosquitoes and then summarize the mechanisms whereby 20E signaling regulates the physiological processes associated with vector competence and vector abundance. Finally, we discuss the potential of using chemicals targeting 20E signaling to control malaria vectors.

Keywords: 20E agonist; 20E antagonist; Chemical control; Insecticide resistance; Steroid hormone; Synergists; Vector abundance; Vector competence.

Fig. 1

20-Hydroxyecdysone (20E) signaling in insects. a 20E biosynthesis from dietary cholesterol, based on studies in Drosophila melanogaster. Metabolites and enzymes are indicated in black and pink, respectively. The “black box” (where the exact metabolites/enzymes are unknown) is indicated by the grey area. Orthologues of these enzymes have been characterized in mosquitoes. b Once 20E binds to its heterodimer EcR/USP receptor, the latter is activated and acts as a transcription factor, binding to an enhancer region known as the ecdysone response elements (EcRE). Binding of EcR/USP to EcRE activates the transcription of early genes (E75, E74, HR3 and Broad-Complex). These four early genes in turn act as transcription factors, inducing or repressing the expression of downstream genes involved in vector competence and vector abundance. Br-C Broad complex, EcR ecdysone receptor, USP ultraspiracle

Fig. 2

Manipulating 20E titers, activity or signaling affects several physiological processes at each stage of a mosquito life-cycle. Only processes that have been experimentally confirmed in mosquitoes are represented. The asterisk (*) indicates that this is not the role of 20E in males, but rather the role that the male-secreted 20E plays in females, once it is transferred to their atrium during mating

Fig. 3

Anautogenous mosquitoes use the blood nutrients to produce egg components in the fat body. In Aedes aegypti, digestion of the blood meal involves several metabolic processes (indicated in boxes), many of which are regulated by 20E signaling, as indicated by the “20E” label. The carbohydrate-related metabolic pathways are indicated in green boxes, while the lipid-related metabolic pathways are indicated in red boxes. CoA Coenzyme A, TAGs triacylglycerols, TOR target of rapamycin

Fig. 4

20E signaling regulates oogenesis (for details see text). The steps regulated by 20E signaling in mosquitoes are indicated by orange asterisks (*) OEH Ovary ecdysteroidogenic hormone, ILP insulin-like peptide, YPPs yolk protein precursors