Influenza D viruses in polymicrobial infections

Abstract

Influenza D viruses (IDVs) comprise Deltainfluenzaviridae, the newest genus of the Orthomyxoviridae family. This group of viruses primarily infects the upper respiratory tract and causes only mild symptoms. Unlike most influenza viruses, IDVs infect a wide range of ungulates, including cattle, swine, and sheep. In cattle, IDVs are thought to act as an etiologic agent in bovine respiratory disease (BRD), a severe polymicrobial disease primarily impacting calves. In chapters 2-4 of this thesis, we report the first experimental infection of an IDV in sheep with and without a recent Mycoplasma ovipneumoniae (M. ovipneumoniae) bacterial infection. We found no evidence of overt illness in IDV-infected lambs. Our findings suggested that recent M. ovipneumoniae infection induced a mild proinflammatory innate immune response that contributed to an enhanced neutralizing antibody response compared to that of M. ovipneumoniae-naive IDV-infected lambs. These findings suggest that although these lambs did not present with clinical symptoms in response to IDV, carriage could contribute to the inflammatory response in sheep experiencing polymicrobial infections. Influenza infections can confer short-term protection against additional viral pathogens. This process, called heterologous viral interference, is mediated by type I interferon antiviral signaling. This phenomenon predominantly occurs when a host is infected with a mild virus followed by a more severe virus. In humans, heterologous viral interference can result in an attenuation or delay of symptoms associated with the more severe pathogen. Evidence suggests that IDVs infect humans, although there is no evidence that these infections are symptomatic. To gain insight into whether IDVs can reduce the symptoms of influenza A virus (IAV), we performed a series of experiments in mice. In Chapter 5 of this thesis we show that IDV infection can, but does not always, reduce disease associated with IAV. We subsequently sought to identify critical type I interferon signaling events underlaying this phenomenon, but our results remain inconclusive.