Dissemination of influenza B virus to the lower respiratory tract of mice is restricted by the interferon response

The global burden of disease caused by Influenza B virus (IBV) is substantial, however IBVs remain overlooked. Understanding host-pathogen interactions as well as establishing physiologically relevant models of infection are important for the development and assessment of therapeutics and vaccines against IBV. Here, we assessed an upper respiratory tract (URT)-restricted model of mouse IBV infection, comparing it to the conventional administration of virus to the total respiratory tract (TRT). We found that URT infections with different strains of IBV resulted in limited dissemination of IBV to the lungs. Infection of the URT did not result in weight loss or systemic inflammation even at high inoculum doses and despite robust viral replication in the nose. Dissemination of IBV to the lung was enhanced in mice lacking functional type I IFN receptor (IFNAR2) but not IFN{gamma}. Conversely, in mice expressing the IFN-inducible gene Mx1 we found reduced IBV replication in the lung and reduced dissemination of IBV from the URT to the lung. Both URT and TRT inoculation with IBV resulted in seroconversion against IBV. However, priming at the TRT conferred superior protection from a heterologous lethal IBV challenge compared to URT priming, as determined by improved survival rates and reduced viral replication throughout the respiratory tract. Overall, our study establishes a URT-restricted IBV infection model, highlights the critical role of IFNs in limiting dissemination of IBV to the lungs but also demonstrates that the lack of viral replication in the lung may impact protection from subsequent infections. ImportanceOur study investigated how IBV spreads from the nose to the lung of mice, the impact this has on disease and protection from re-infection. We found that when applied to the nose only, IBV does not spread very efficiently to the lungs in a process controlled by the interferon response. Priming immunity at the nose only was less protective from re-infection than priming immunity at both the nose and lung. These insights can guide the development of potential therapies targeting the interferon response as well as of intranasal vaccines against IBV.