Role Of Danger-associated Molecular Patterns Research Articles

The PB1-F2 protein of influenza A virus induces danger molecule accumulation in infected lungs, priming for an enhanced inflammatory response to bacterial pneumonia (P6162)

Abstract We recently described a signaling pathway, CD24-Siglecg G/10, that suppresses the inflammatory response to danger-associated molecular patterns (DAMPs). Here we report on the role of DAMPs in secondary bacterial pneumonia following influenza A virus (IAV) infection. During IAV infection, two prototypical DAMPs, HSP70 and HMGB1, accumulated in the lungs of infected mice. IAV PB1-F2, a protein encoded by highly-pathogenic strains, such as 1918 “Spanish flu,” contributed to this accumulation, as infection with PB1-F2-deficient IAV led to a decrease in DAMPs. To model bacterial superinfection, we administered sublethal LPS intranasally 7 days after IAV infection. While all mice were more sensitive to the LPS challenge after IAV infection, CD24-/- and siglecg-/- mice did not recover from LPS challenge as quickly as WT mice. Indeed, this regimen was lethal for a subset of knockout mice, while all WT mice survived. Furthermore, CD24- and Siglec G-deficient mice were more susceptible to superinfection with the gram-negative bacterium Haemophilus influenzae. Together these results demonstrate that the ability of inflammatory PB1-F2 protein of IAV to prime for lethal, secondary bacterial pneumonia is due to the accumulation of DAMPs in the lungs of infected animals, and provide new targets for the treatment of this often fatal disease.