Active Influenza D coinfection reduces Influenza A disease severity in mice

Abstract 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.