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However, it remains unclear about the underlying molecular mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We established a mouse model of post\u2010influenza <jats:italic>S aureus<\/jats:italic> pneumonia using conditional <jats:italic>Shp2<\/jats:italic> knockout mice (<jats:italic>LysM<jats:sup>Cre\/+<\/jats:sup>:Shp2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic>). The survival, bacterial clearance, pulmonary histology, phenotype of macrophages,\u00a0and expression of type I interferons and chemokines were assessed between SHP2 deletion and control mice (<jats:italic>Shp2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic>). We infused additional KC and MIP\u20102 to examine the reconstitution of antibacterial immune response in <jats:italic>LysM<jats:sup>Cre\/+<\/jats:sup>:Shp2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice. The effect of SHP2 on signal molecules including MAPKs (JNK, p38 and Erk1\/2), NF\u2010\u03baB p65 and IRF3 was further detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>LysM<jats:sup>Cre\/+<\/jats:sup>:Shp2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice displayed impaired antibacterial immunity and high mortality compared with control mice in post\u2010influenza <jats:italic>S aureus<\/jats:italic> pneumonia. The attenuated antibacterial ability was associated with the induction of type I interferon and suppression of chemo\u2010attractants KC and MIP\u20102, which reduced the infiltration of neutrophils into the lung upon secondary bacterial invasion. In additional, <jats:italic>Shp2<\/jats:italic> knockout mice displayed enhanced polarization to alternatively activated macrophages (M2 phenotype). Further in <jats:italic>vitro<\/jats:italic> analyses consistently demonstrated that SHP2\u2010deficient 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\u2010\u03baB and IRF3 signalling in macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings reveal that the SHP2 expression enhances the host immune response and prompts bacterial clearance in post\u2010influenza <jats:italic>S aureus<\/jats:italic> pneumonia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.12721","type":"journal-article","created":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T14:46:35Z","timestamp":1575038795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["SHP2 deficiency promotes <scp><i>Staphylococcus aureus<\/i><\/scp> pneumonia following influenza infection"],"prefix":"10.1111","volume":"53","author":[{"given":"Wei","family":"Ouyang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyan","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5764-6628","authenticated-orcid":false,"given":"Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,11,29]]},"reference":[{"issue":"2","key":"e_1_2_9_2_1","first-page":"223","article-title":"The chronicle of influenza epidemics","volume":"13","author":"Beveridge WI","year":"1991","journal-title":"Hist Philos Life 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