SHP2 deficiency promotes Staphylococcus aureus pneumonia following influenza infection.

OBJECTIVES

Secondary bacterial pneumonia is common following influenza infection. However, it remains unclear about the underlying molecular mechanisms.

MATERIALS AND METHODS

We established a mouse model of post-influenza S aureus pneumonia using conditional Shp2 knockout mice (LysM :Shp2 ). The survival, bacterial clearance, pulmonary histology, phenotype of macrophages, and expression of type I interferons and chemokines were assessed between SHP2 deletion and control mice (Shp2 ). We infused additional KC and MIP-2 to examine the reconstitution of antibacterial immune response in LysM :Shp2 mice. The effect of SHP2 on signal molecules including MAPKs (JNK, p38 and Erk1/2), NF-κB p65 and IRF3 was further detected.

RESULTS

LysM :Shp2 mice displayed impaired antibacterial immunity and high mortality compared with control mice in post-influenza S aureus pneumonia. The attenuated antibacterial ability was associated with the induction of type I interferon and suppression of chemo-attractants KC and MIP-2, which reduced the infiltration of neutrophils into the lung upon secondary bacterial invasion. In additional, Shp2 knockout mice displayed enhanced polarization to alternatively activated macrophages (M2 phenotype). Further in vitro analyses consistently demonstrated that SHP2-deficient macrophages were skewed towards an M2 phenotype and had a decreased antibacterial capacity. Moreover, SHP2 modulated the inflammatory response to secondary bacterial infection via interfering with NF-κB and IRF3 signalling in macrophages.

CONCLUSIONS

Our findings reveal that the SHP2 expression enhances the host immune response and prompts bacterial clearance in post-influenza S aureus pneumonia.