Abstract
The Malpighian tubules and hindgut are the renal excretory tissues of mosquitoes; they are essential to maintaining hemolymph water and solute homeostasis. Moreover, they make important contributions to detoxifying metabolic wastes and xenobiotics in the hemolymph. We have focused on elucidating the molecular mechanisms of Malpighian tubule function in adult female mosquitoes and developing chemical tools as prototypes for next-generation mosquitocides that would act via a novel mechanism of action (i.e., renal failure). To date, we have targeted inward rectifier potassium (Kir) channels expressed in the Malpighian tubules of the yellow fever mosquito Aedes aegypti and malaria mosquito Anopheles gambiae. Inhibition of these channels with small molecules inhibits transepithelial K+ and fluid secretion in Malpighian tubules, leading to a disruption of hemolymph K+ and fluid homeostasis in adult female mosquitoes. In addition, we have used next-generation sequencing to characterize the transcriptome of Malpighian tubules in the Asian tiger mosquito Aedes albopictus, before and after blood meals, to reveal new molecular targets for potentially disrupting Malpighian tubule function. Within 24 h after a blood meal, the Malpighian tubules enhance the mRNA expression of genes encoding mechanisms involved with the detoxification of metabolic wastes produced during blood digestion (e.g., heme, NH3, reactive oxygen species). The development of chemical tools targeting these molecular mechanisms in Malpighian tubules may offer a promising avenue for the development of mosquitocides that are highly-selective against hematophagous females, which are the only life stage that transmits pathogens.
Highlights
Adult female mosquitoes are vectors of numerous pathogens that cause diseases of significance to global health
It is with this vision in mind that motivated a collaborative effort by the Piermarini (The Ohio State University), Beyenbach (Cornell University), and Denton (Vanderbilt University) laboratories to identify K+ channels expressed in the Malpighian tubules of adult female mosquitoes and develop small-molecule inhibitors of these channels to disrupt the capacity of Malpighian tubules to produce urine, with the ultimate aim of disrupting K+ and fluid homeostasis in mosquitoes
To confirm that the above effects on Malpighian tubules and mosquitoes were specific to the inhibition of AeKir1, we developed so-called “inactive” analogs of each molecule that do not inhibit
Summary
Adult female mosquitoes are vectors of numerous pathogens that cause diseases of significance to global health. Most insecticides used for mosquito control target the nervous system, such as pyrethroids, carbamates, organophosphates, and organochlorides These neurotoxins are highly effective at killing mosquitoes, the overuse of a limited number of active compounds has exerted a strong, selective pressure for traits that make mosquitoes resistant to conventional insecticides (e.g., knockdown resistance mutations, elevated detoxification mechanisms) [5], analogous to the evolution of antibiotic resistance in pathogenic bacteria. The Malpighian tubules offer a potential physiological target to exploit for developing insecticides that have novel mechanisms of action, but may be highly selective to hematophagous adult females. The following pages highlight recent efforts by our group to understand the basic molecular mechanisms of Malpighian tubule function in adult female mosquitoes with the ultimate aim of developing novel mosquitocides
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