Date Published: December 15, 2016
Publisher: Public Library of Science
Author(s): Lauren M. Childs, Francisco Y. Cai, Evdoxia G. Kakani, Sara N. Mitchell, Doug Paton, Paolo Gabrieli, Caroline O. Buckee, Flaminia Catteruccia, David S. Schneider.
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.
Despite recent progress in combating the malaria parasite, nearly 200 million infections and around 500,000 deaths are caused by malaria annually, mostly in young children in sub-Saharan Africa [1, 2]. Even with new drugs and vaccines in the research pipeline , control of the Anopheles species that transmit human malaria remains the cornerstone of prevention and transmission reduction efforts [2, 4]. Of the four classes of insecticides available for malaria control, pyrethroids are the only compounds approved for use on long-lasting insecticide-impregnated bed nets (LLINs), due to their relatively low toxicity, and they are heavily used in indoor residual spray (IRS) programs . This is a major limitation, as the increased application of both interventions over the last decade has inevitably led to the emergence and spread of insecticide resistance in natural mosquito populations. Indeed, resistance to pyrethroids has been observed in most Anopheles populations from sub-Saharan Africa , making the identification of alternative non-toxic compounds that can reduce parasite transmission a high priority in the malaria control agenda .
The development of non-toxic compounds that target the mosquito vector in novel ways will be essential for achieving malaria elimination goals . Our study identifies steroid hormone signaling as a promising new target that can provide an effective and complementary approach to existing tools for vector control. Although our data are based on topical application, and therefore cannot directly be extrapolated to effectiveness in field settings, we observed a robust, dose-dependent impact of the steroid hormone agonist DBH on egg development, insemination rates, and adult female longevity in experimental applications. Moreover, DBH strongly prevented the development of the deadliest human malaria parasite, P. falciparum, a highly desirable feature for any compound used in malaria control strategies. While the effects on fecundity, insemination rates, and longevity are in agreement with previous studies linking high 20E activity to apoptosis of ovarian follicles [28, 29], reduced mating receptivity  and premature aging [30, 31], the observed reduction in P. falciparum infections was completely unexpected. In future studies it will be important to test steroid hormone agonists under field conditions, using different mosquito strains and parasite isolates, and to determine whether the effects on oogenesis and parasite development are linked, for example, via the induction of immune pathways.