Influenza D viruses (IDV) are known to co-circulate with viral and bacterial pathogens in cattle and other ruminants. Currently, there is limited knowledge regarding host responses to IDV infection and whether IDV infection affects host susceptibility to secondary bacterial infections. To begin to address this gap in knowledge, the current study utilized a combination of in vivo and in vitro approaches to evaluate host cellular responses against primary IDV infection and secondary bacterial infection with Staphylococcus aureus (S. aureus). Primary IDV infection in mice did not result in clinical signs of disease and it did not enhance the susceptibility to secondary S. aureus infection. Rather, IDV infection appeared to protect mice from the usual clinical features of secondary bacterial infection, as demonstrated by improved weight loss, survival, and recovery when compared to S. aureus infection alone. We found a notable increase in IFN-β expression following IDV infection while utilizing human alveolar epithelial A549 cells to analyze early anti-viral responses to IDV infection. These results demonstrate for the first time that IDV infection does not increase the susceptibility to secondary bacterial infection with S. aureus, with evidence that anti-viral immune responses during IDV infection might protect the host against these potentially deadly outcomes.

The newest type of influenza virus, influenza D virus (IDV), was isolated in 2011. IDV circulates in several animal species worldwide, causing mild respiratory illness in its natural hosts. Importantly, IDV does not cause clinical disease in humans and does not spread easily from person to person. Here, we review what is known about the host–pathogen interactions that may limit IDV illness. We focus on early immune interactions between the virus and infected host cells in our summary of what is known about IDV pathogenesis. This work establishes a foundation for future research into IDV infection and immunity in mammalian hosts.

Influenza D virus (IDV), the only member of the fourth genus of the Orthomyxoviridae family, primarily infects bovines. While no symptoms have been identified in humans, studies find seropositivity rates up to 95% among people with close contact to cattle. This suggests that IDV may cocirculate in human populations with Influenza A viruses (IAV). Clinical data indicate that coinfections with some mild respiratory viruses, such as rhinovirus, can reduce IAV severity. The current study investigates whether and how the immune response to preceding IDV infection affects the outcome of subsequent IAV. Previously we reported that IDV stimulates strong IFN-β production in mice and in human epithelium (A549 cells). We extend these findings by showing that IDV productively infects respiratory tract of wild-type (WT) mice and induces recruitment of innate and adaptive immune cells to the lungs. IDV-IAV coinfected mice exhibit a stronger IFN-β response early in IAV infection compared to mice infected with IAV alone. Consistently, IDV-infected WT mice showed less weight loss and improved survival after IAV. To better understand the role of type I IFN signaling in host response during IDV and IAV coinfection, we used mice deficient in either subunit of type I IFN receptor (Ifnar1−/−, Ifnar2−/−). While IDV-infected WT mice exhibit only slight weight loss occurring mid-infection, Ifnar1−/− mice exhibit dramatic weight loss mid-infection but recover fully within 3 days. In contrast to its effect in WT mice, IDV exacerbated IAV-induced mortality and lengthened the duration of symptoms in Ifnar1−/− and Ifnar2−/− mice. Our results show that active IDV infection elicits a type I IFN-dependent protection against IAV-associated weight loss and mortality.