Pathophysiology of Influenza D Virus Infection in Specific-Pathogen-Free Lambs with or Without Prior Exposure

Polymicrobial pneumonias occur frequently in cattle, swine, and sheep, resulting in major economic losses. Individual pathogens comprising these complex infections may be mild on their own but can instead exhibit synergism or increase host susceptibility. Two examples of such pathogens, () and influenza D viruses (IDVs), naturally infect domestic sheep. In sheep, the role of in chronic nonprogressive pneumonia is well-established, but the pathogenesis of IDV infection has not previously been studied. We utilized a specific-pathogen-free sheep flock to study the clinical response to IDV infection in naïve vs. -exposed lambs. Lambs were inoculated intranasally with or mock infection, followed after four weeks by infection with IDV. Pathogen shedding was tracked, and immunological responses were evaluated by measuring acute phase response and IDV-neutralizing antibody titers. While lamb health statuses remained subclinical, -exposed lambs had significantly elevated body temperatures during IDV infection compared to -naïve, IDV-infected lambs. Moreover, we found a positive correlation between prior burden, early-infection IDV shedding, and IDV-neutralizing antibody response. Our findings suggest that IDV infection may not induce clinical symptoms in domestic sheep, but previous exposure may promote mild IDV-associated inflammation.