Abstract
Coronaviruses and influenza A viruses are major respiratory pathogens with pandemic potential. Using pigs as a translational large-animal model, we compare the virulence, pathogenesis, and immune responses to porcine respiratory coronavirus (PRCV) and pandemic H1N1 2009 influenza virus (pH1N1). Here we show that PRCV induces higher viral load and prolonged viral shedding, stronger systemic and mucosal T cell activation, expansion of memory B cells, and distinct nasal microbiome changes. In contrast, pH1N1 results in rapid neutralising antibody production, robust Tfh and germinal centre B cell responses, and broader early nasal microbial diversity. Transcriptional responses to PRCV and pH1N1 infection start with the activation of shared interferon-stimulated genes but later diverge as pathways involving stromal-immune interactions and vascular integrity shapes lung pathology and subsequent immune responses. These findings demonstrate fundamental differences in coronavirus and influenza virus-host interactions and establish the pig as a powerful comparative model for studying respiratory virus pathogenesis and immunity.