Lack of IFNγ signaling attenuates spread of influenza A virus in vivo and leads to reduced pathogenesis.

IFNγ is a key regulator of inflammatory responses but its role in influenza A virus (IAV) pathogenesis is unclear. Our studies show that infection of mice lacking the IFNγ receptor (IFNγR(-/-)) at a dose which caused severe disease in wild type 129 Sv/Ev (WT) mice resulted in milder clinical symptoms and significantly lower lung virus titers by 6 days post-infection (dpi). Viral spread was reduced in IFNγR(-/-) lungs at 2 and 4 dpi. Levels of inflammatory cytokines and chemokines were lower in IFNγR(-/-) mice at 2 dpi and there was less infiltration of monocyte/macrophage lineage cells than in WT mice. There was no difference in CD4(+) and CD8(+) T cells and alveolar macrophages in the bronchoalveolar lavage fluid (BALF) at 2 and 4 dpi but by 4 dpi IFNγR(-/-) mice had significantly higher percentages of neutrophils. Our data strongly suggest that IAV can use the inflammatory response to promote viral spread.