Pathogenesis of Influenza D Virus in Cattle

Cattle have been proposed as the natural reservoir of a novel member of the virus family Orthomyxoviridae, which has been tentatively classified as influenza D virus (IDV). Although isolated from sick animals, it is unclear whether IDV causes any clinical disease in cattle. To address this aspect of Koch's postulates, three dairy calves (treatment animals) held in individual pens were inoculated intranasally with IDV strain D/bovine/Mississippi/C00046N/2014. At 1 day postinoculation, a seronegative calf (contact animal) was added to each of the treatment animal pens. The cattle in both treatment and contact groups seroconverted, and virus was detected in their respiratory tracts. Histologically, there was a significant increase in neutrophil tracking in tracheal epithelia of the treatment calves compared to control animals. While infected and contact animals demonstrated various symptoms of respiratory tract infection, they were mild, and the calves in the treatment group did not differ from the controls in terms of heart rate, respiratory rate, or rectal temperature. To mimic zoonotic transmission, two ferrets were exposed to a plastic toy fomite soaked with infected nasal discharge from the treatment calves. These ferrets did not shed the virus or seroconvert. In summary, this study demonstrates that IDV causes a mild respiratory disease upon experimental infection of cattle and can be transmitted effectively among cattle by in-pen contact, but not from cattle to ferrets through fomite exposure. These findings support the hypothesis that cattle are a natural reservoir for the virus. IMPORTANCE A novel influenza virus, tentatively classified as influenza D virus (IDV), was identified in swine, cattle, sheep, and goats. Among these hosts, cattle have been proposed as the natural reservoir. In this study, we show that cattle experimentally infected with IDV can shed virus and transmit it to other cattle through direct contact, but not to ferrets through fomite routes. IDV caused minor clinical signs in the infected cattle, fulfilling another of Koch's postulates for this novel agent, although other objective clinical endpoints were not different from those of control animals. Although the disease observed was mild, IDV induced neutrophil tracking and epithelial attenuation in cattle trachea, which could facilitate coinfection with other pathogens, and in doing so, predispose animals to bovine respiratory disease.