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Significance Influenza A virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. Here, we used single-cycle replication reporter viruses to analyze the early cellular response to influenza infection in vivo. This approach revealed distinct tiers of antiviral responses that were associated with the magnitude of virus replication. We also unveiled disparate protection of epithelial cell types mediated by interferon during virus spread. These results demonstrate the early landscape of virus–host interactions in vivo with the magnitude and round of replication revealing distinct antiviral signatures and responses.

Distinct antiviral signatures revealed by the magnitude and round of influenza virus replication in vivo