Small-molecule inhibitors of inward rectifier potassium (Kir) channels reduce bloodmeal feeding and have insecticidal activity against the horn fly (Diptera: Muscidae)

Authors: LI, ZHILIN - Louisiana State University Agcenter; GUERRERO, FELIX - Retired ARS Employee; Perez De Leon, Adalberto - Beto; FOIL, LANE - Louisiana State University Agcenter; SWALE, DANIEL - Louisiana State University Agcenter

Submitted to: Journal of Medical Entomology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2020
Publication Date: 2/1/2020
Citation: Li, Z., Guerrero, F., Perez De Leon, A.A., Foil, L.D., Swale, D.R. 2020. Small-molecule inhibitors of inward rectifier potassium (Kir) channels reduce bloodmeal feeding and have insecticidal activity against the horn fly (Diptera: Muscidae). Journal of Medical Entomology. 57(4):1131-1140. https://doi.org/10.1093/jme/tjaa015.
DOI: https://doi.org/10.1093/jme/tjaa015

Interpretive Summary: The horn fly is an external parasite that feeds on the blood of cattle. This is one of the most economically important biting flies affecting cattle in North America. Blood feeding by horn flies results in reduced milk production and the associated blood loss can prevent weight gain of calves and yearlings. Resistance to the majority of commercialized insecticides reduces the efficacy of current control programs that rely on chemical treatment. Research is needed to discover targets for the development of safer insecticides with new modes of action that can be used to control horn flies efficiently. Salivary gland and Malpighian tubule function are critical for horn fly survivorship as they drive bloodmeal acquisition and maintain steady internal fluid conditions during blood meal processing, respectively. Inward rectifier potassium (Kir) channels play important roles in the function of insects. Experiments were conducted to test the hypothesis that the modulation of Kir channels in the horn fly would preclude blood feeding and induce mortality by reducing the secretory activity of the salivary gland while simultaneously inducing Malpighian tubule failure. Experimental results showed that structurally diverse Kir channel modulators reduced the secretory activity of the salivary gland by up to 5-fold when compared to control. This reduction in saliva secretion correlated with a reduction in blood meal acquisition in adult flies. Additionally, adult feeding on blood treated with Kir channel modulators resulted in significant mortality. These experimental results validated the Kir channels of H. irritans as putative insecticide targets. Scientific knowledge gained from this study could be applied to develop novel therapeutic technologies targeting salivary gland or Malpighian tubule function to reduce the economic burden of horn fly ectoparasitism on cattle health and production.

Technical Abstract: Bloodmeal feeding by the horn fly, Haematobia irritans (L.), is associated with reduced milk production and blood loss that ultimately prevents weight gain of calves and yearlings, thus blood feeding by H. irritans causes significant economic losses in several continents. As with other arthropods, resistance to the majority of commercialized insecticides reduces the efficacy of current control programs. Thus, innovative technologies and novel biochemical targets for horn fly control are needed. Salivary gland and Malpighian tubule function are critical for H. irritans survivorship as they drive bloodmeal acquisition and maintain ion- and fluid-homeostasis during blood meal processing, respectively. Experiments were conducted to test the hypothesis that pharmacological modulation of H. irritans inward rectifier potassium (Kir) channels would preclude blood feeding and induce mortality by reducing the secretory activity of the salivary gland while simultaneously inducing Malpighian tubule failure. Experimental results clearly indicate structurally diverse Kir channel modulators reduce the secretory activity of the salivary gland by up to 5-fold when compared to control and the reduced saliva secretion was highly correlated to a reduction in blood meal acquisition in adult flies. Furthermore, adult feeding on blood treated with Kir channel modulators resulted in significant mortality. In addition to validating the Kir channels of H. irritans as putative insecticide targets, the knowledge gained from this study could be applied to develop novel therapeutic technologies targeting salivary gland or Malpighian tubule function to reduce the economic burden of horn fly ectoparasitism on cattle health and production.