Open AccessSHP2 deficiency promotes Staphylococcus aureus pneumonia following influenza infection
Author(s) -
Ouyang Wei,
Liu Chao,
Pan Ying,
Han Yu,
Yang Liping,
Xia Jingyan,
Xu Feng
Publication year - 2020
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12721
Subject(s) - microbiology and biotechnology , immune system , staphylococcus aureus , chemokine , biology , immunology , irf3 , conditional gene knockout , pneumonia , influenza a virus , innate immune system , phenotype , medicine , bacteria , gene , virus , genetics , biochemistry
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 Cre/+ :Shp2 flox/flox ). 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 flox/flox ). We infused additional KC and MIP‐2 to examine the reconstitution of antibacterial immune response in LysM Cre/+ :Shp2 flox/flox 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 Cre/+ :Shp2 flox/flox 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.