Disrupting Mosquito Reproduction and Parasite Development for Malaria Control

Abstract

The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance.

Steroid hormone agonists reduce female fitness in insecticide-resistantAnophelespopulations

“…Following on from earlier laboratory studies that demonstrated that topical application of the 20E agonist methoxyfenozide caused sterility and a reduction in lifespan in female An. gambiae mosquitoes (Childs et al, 2016), we demonstrate that this chemistry has a similar effect on multiple insecticide resistant Anopheles populations. Crucially, we also show that, with the addition of the adjuvant RME, methoxyfenozide interrupts egg development through tarsal contact Furthermore, blood fed females had a significant reduction in life span post methoxyfenozide exposure.…”

“…An 8% stock solution of the compound methoxyfenozide (MET) (Sigma-Aldrich) was prepared in DMSO; this stock was diluted in acetone to a 0.4% to match the concentration used in previous studies (Childs et al, 2016). Mosquitoes were anesthetized using carbon dioxide, placed on a petri dish lined with filter paper with the thorax exposed and held on a 4°C chill table (BioQuip products, Rancho Dominguez, CA).…”

“…Recently, a 20-hydroxyecdysone (20E) agonist, methoxyfenozide (MET), was shown to impact multiple aspects of Anopheles biology that are relevant to its ability to carry and transmit Plasmodium (Childs et al, 2016). 20E is a major steroid hormone that, in multiple Anopheles species, is important for the reproductive fitness of adult male mosquitoes (Pondeville et al, 2008), alongside its conserved roles in adult female oogenesis (Baldini et al, 2013;Klowden and Russell, 2004) and larval development (Gilbert and Rewitz, 2009).…”

“…gambiae females (G3 strain) induced a multimodal cascade of effects comprising substantially reduced lifespan and fecundity, reduced mating susceptibility, and partial blockage of Plasmodium falciparum transmission (Childs et al, 2016). Mathematical modelling predicted that, due to the combined effect on multiple traits, the use of MET as a vector control tool could produce comparable reductions in malaria burden to insecticide-based vector control (Childs et al, 2016). However, to be effective in the field, proposed new chemistries for incorporation into LLINs must overcome two key challenges.…”

Evolution of sexually-transferred steroids inAnophelesmosquitoes

“…http://dx.doi.org/10.1101/248112 doi: bioRxiv preprint first posted online Jan. 15, 2018; field use of 20E receptor agonists has been recently proposed to reduce malaria transmission (17). However, a limited number of Anopheles species have been studied.…”