Abstract
What determines host infectiousness during influenza A virus (IAV) infection remains a fundamental unanswered question in virology. While upper respiratory tract (URT) replication is necessary for transmission, it's insufficient to explain host-to-host variation in contagiousness. Using the infant mouse model of influenza transmission, we show that viruses containing H3 hemagglutinin shed at higher levels than non-H3-containing viruses, despite comparable URT replication. H3-containing virus infection was associated with higher URT inflammation, characterized by increased cytokine production, immune cell recruitment, and mucus hypersecretion, which directly correlated with shedding efficiency. Transcriptomic profiling identified enrichment of interferon-stimulated gene programs, with a dominant interferon gamma (IFNγ) signature during H3 infections. Functional studies demonstrated that IFNγ deficiency reduced mucus production, shedding, and transmission, whereas IFNγ supplementation restored these phenotypes. Together, these findings identify IFNγ-driven mucosal inflammation key host determinant of influenza infectiousness, reframing contagiousness as a consequence of host inflammatory clearance rather than viral replication alone.