IFNL3 reduces replication of CIRDC-associated viruses in canine airway epithelial cells

Canine infectious respiratory disease complex (CIRDC) causes contagious respiratory disease in dogs and encompasses several etiologic agents. Viral pathogens associated with CIRDC include canine adenovirus type 2 (CAV-2), canine distemper virus (CDV), canine herpesvirus-1 (CaHV-1) and canine influenza virus (CIV). Vaccine availability and efficacy vary and there are currently no antivirals available for treatment. Interferons (IFNs) are at the frontline of the immune defense against many viral infections and interferon lambda (IFNL) has shown to be a potent antiviral. We hypothesized that canine interferon lambda-3 (IFNL3) treatment of canine respiratory epithelial cells (ALI-CRECs) will reduce replication of kennel cough viruses. ALI-CRECs were isolated, cultured and characterized morphologically and immunologically prior to infection with CDV, CaHV-1, CIV and CAV-2. The value of canine IFNL3 treatment for reducing viral titers as well as induction of interferon responses were evaluated for each virus. Treatment of ALI-CRECs with IFNL3 induced the expression of interferon stimulated genes. In addition, prophylactic IFNL3 administration resulted in a reduction in viral DNA with CT value changes of up to 13 intracellularly and up to 9 extracellularly. In contrast, for CDV and CaHV-1 a reduction in viral RNA/DNA was observed only intracellularly with CT value changes of up to 11 and up to 4 respectively. Prophylactic IFNL3 treatment also significantly reduced viral titers 1.2 to 3 log-fold for CAV-2, 0.9-2.5 log-fold for CDV, and 1.1-1.7 log-fold for CaHV-1. No effect of IFNL3 was observed for CIV RNA and CIV viral titers. Coinciding with a reduction in viral replication, interferon stimulated genes were differentially expressed in interferon treated and infected cells when compared with controls. In conclusion, ALI-CRECs have shown to be excellent systems to study respiratory viruses and evaluate the potential antiviral effect of IFNL3. However further in-depth mechanistic studies are needed to fully understand how IFNL3 stimulates/modulates local immune responses to induce antiviral effects. Moreover, while this study highlights the potential antiviral efficacy of IFNL3 for several canine respiratory viruses, determination of safety, effective doses in vivo as well as therapeutic potential will have to be evaluated in dogs.