Anti-Influenza D immunity contributes to improved survival after secondary bacterial infection in mice

Abstract

Clinical evidence suggest that the newly emerging Influenza D viruses (IDV) co-circulate in humans with influenza A viruses (IAV). However, how IDV contributes to human disease is currently not known. Because IAV is known to create a suppressive environment permissive to development of life threatening secondary bacterial infection (SBI), it is important to understand whether IDV affects the host immune response to IAV and to SBIs. Using a combination of in vivo and ex vivo approaches we evaluated host immune responses to both primary pulmonary IDV infection and subsequent SBI with Staphylococcus aureus in mice. Consistent with lack of disease symptoms in humans, we found that IDV infection did not induce clinical signs of disease in WT mice, evidenced by no weight loss or morbidity/mortality. Contrary to IAV that is known to increase susceptibility to SBI at least partially by inhibiting type I interferon (IFN) signaling, we found that IDV infection appeared to protect mice from the typical clinical features of SBI, as demonstrated by improved weight loss, survival (100% vs 60%), and recovery when compared to S. aureus-infection alone. Consistent with our previous report of IFN-beta reducing SBI susceptibility, we found that IDV induced production of IFN-b. We also found that IDV infection resulted in increased weight loss and morbidity in mice deficient in type I IFN receptor subunit 2 (Ifnar2−/−), but not in Ifnar1−/− mice suggesting a role for IFN-b signaling through Ifnar2 in IDV anti-viral immunity. Thus, our results demonstrate for the first time that IDV infection does not increase the susceptibility to SBI with S. aureus in mice, with evidence that anti-IDV immune responses might protect the host from these potentially deadly SBIs.