Interleukin (IL)-22 has redundant, protective or pathogenic functions during auto-immune, inflammatory and infectious diseases. Here, we addressed the potential role of IL-22 in host defence and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection.

We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that RORγt-positive αβ and γδ T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as two days post-infection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22 deficient animals had an enhanced lung injury and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs.

Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection where it limits lung inflammation and subsequent bacterial superinfections.