Potassium ion channels as a druggable target to inhibit viral replication in honey bees

Authors: FELLOWS, CHRISTOPHER - Louisiana State University; Simone-Finstrom, Michael; ANDERSTON, TROY - University Of Nebraska; SWALE, DANIEL - University Of Florida

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/16/2023
Publication Date: 6/22/2023
Citation: Fellows, C., Simone-Finstrom, M., Anderston, T., Swale, D. 2023. Potassium ion channels as a druggable target to inhibit viral replication in honey bees. Virology. 20(134):1-17. https://doi.org/10.1186/s12985-023-02104-0.
DOI: https://doi.org/10.1186/s12985-023-02104-0

Interpretive Summary: The main driver of issues related to honey bee health is the parasitic Varroa mite and the viruses it vectors. However, there are no current treatments available to reduce the impacts of viral infection. We present results testing the use of drugs that target potassium (KATP) channels as a target for reducing virus-mediated mortality and viral replication in bees as well as increasing colony-level immunity. Bees provided KATP channel activators had lower mortality after Israeli Acute Paralysis virus (IAPV) infection that was not different from uninfected bees. Furthermore, we show the generation of reactive oxygen species (ROS) can stimulate antiviral immune responses and ROS concentrations in bees are regulated by KATP channels, which highlights a potential mechanism regulating the bee immune system. Next, we tested the influence of antiviral drug activation of KATP channels to infection of 6 viruses at the colony level in the field. Data strongly support that KATP channels are a field-relevant target site as pinacidil treated colonies displayed reduced virus titers by up to 75-fold across 6 different viruses that were not significantly different than non-inoculated colonies. Together, these data indicate a functional linkage between KATP channels, ROS, and antiviral defense mechanisms to exist in bees and define a toxicologically relevant pathway that can be used for novel therapeutics development to enhance bee health and colony sustainability in the field.

Technical Abstract: Declines in managed honey bee populations are multifactorial but closely associated with reduced virus immunocompetence and thus, mechanisms to enhance immunocompetence are likely to reduce viral infection rates and increase colony viability. However, gaps in knowledge regarding physiological mechanisms or ‘druggable’ target sites to enhance bee immunocompetence has prevented therapeutics development to reduce virus infection. Our data bridge this knowledge gap by implicating ATP-sensitive inward rectifier potassium (KATP) channels as a pharmacologically tractable target for reducing virus-mediated mortality and viral replication in bees as well as increasing colony-level immunity. Bees provided KATP channel activators had lower mortality after Israeli Acute Paralysis virus (IAPV) infection that was not different from uninfected bees. Furthermore, we show the generation of reactive oxygen species (ROS) can stimulate antiviral immune responses and ROS concentrations in bees are regulated by KATP channels, which highlights a functional framework for physiological regulation of the bee immune system. Next, we tested the influence of pharmacological activation of KATP channels to infection of 6 viruses at the colony level in the field. Data strongly support that KATP channels are a field-relevant target site as pinacidil treated colonies displayed reduced virus titers by up to 75-fold across 6 different viruses that were not significantly different than non-inoculated colonies. Together, these data indicate a functional linkage between KATP channels, ROS, and antiviral defense mechanisms to exist in bees and define a toxicologically relevant pathway that can be used for novel therapeutics development to enhance bee health and colony sustainability in the field.