Potassium ion channels as a molecular target to reduce virus infection and mortality of honey bee colonies

Abstract

Declines in managed honey bee populations are multifactorial but closely associated with reduced virus immunocompetence and thus, mechanisms to enhance immune function 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 identifying 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 an aspect of colony-level immunity. Bees infected with Israeli acute paralysis virus and provided KATP channel activators had similar mortality rates as uninfected bees. Furthermore, we show that generation of reactive oxygen species (ROS) and regulation of ROS concentrations through pharmacological activation of KATP channels can stimulate antiviral responses, highlighting a functional framework for physiological regulation of the bee immune system. Next, we tested the influence of pharmacological activation of KATP channels on infection of 6 viruses at the colony level in the field. Data strongly support that KATP channels are a field-relevant target site as colonies treated with pinacidil, a KATP channel activator, had reduced titers of seven bee-relevant viruses by up to 75-fold and reduced them to levels comparable to non-inoculated colonies. Together, these data indicate a functional linkage between KATP channels, ROS, and antiviral defense mechanisms 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.

Cloning, functional expression, and pharmacological characterization of inwardly rectifying potassium channels (Kir) from Apis mellifera

“…At the molecular level, this regulation is facilitated by inward rectifying potassium channels (Kir channels). Exposure of K ATP channels, a subtype of Kir channels that plays a fundamental role in the viral protection of honeybees 15 , to pharmacological activators induces an increase in immunocompetence and a reduction in mortality associated with viral infections in honeybees 20 . Conversely, several small molecules with insecticidal activity are being developed to target Kir channels and disrupt potassium homeostasis.…”

Reduction of Deformed Wing Virus-B levels in Colonies of the Honey beeApis melliferaafter Queen Vaccination with inactivatedPaenibacillus larvae

“…Studies have shown that activating the RNAi-system by feeding virus-specific dsRNA to larvae or adult bees before infection with DWV or Israeli Acute Paralysis Virus (IAPV) reduces the viral load, mortality, and symptoms resulting from the specific viral infection (Hunter et al, 2010; Desai et al, 2012). Potassium ion channel manipulation has also been proven effective treatment for IAPV (Fellows et al, 2023). Neither of these methods, however, are currently approved for use in the field, and there is no licensed specific treatment or prophylaxis for DWV (Smeele et al, 2023).…”