Respiratory infection with Enterovirus D68 induces severe acute lung inflammation in the pediatric ferret model

Enterovirus D68 (EV-D68) is a reemerging virus that causes severe respiratory disease and polio-like paralysis in children. Here, using a 6-8 weeks old pediatric ferret model, we show that respiratory infection with the 2014 isolate of EV-D68 (US/MO/14-18947) was associated with severe acute respiratory pathology that was characterized by increased airway restriction, cellular infiltration, inducible nitric oxide synthase (iNOS) expression, and apoptosis along with a significant increase in the expression of pro-inflammatory cytokines. All infected ferrets seroconverted with detectable levels of EV-D68 specific binding and neutralizing antibodies in the plasma. Infection was accompanied by a significant increase in the expression of interferon alpha (IFNα) and related genes suggesting a role for potent innate immune responses in acute viral control. These findings were confirmed <i>in vitro</i> using the human lung epithelial cell line A549. Taken together, our studies identify numerous correlates of acute respiratory pathogenesis in an immunocompetent pediatric ferret model that can be used as markers for the development of vaccines and therapeutics.