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Ply has been shown to activate the inflammasome, but also can bind to MRC\u20101 resulting in suppression of dendritic cell inflammatory responses. We have used an in vitro infection model of human monocyte\u2010derived macrophages (MDM), and a mouse model of pneumonia to clarify whether pro\u2010 or anti\u2010inflammatory effects dominate the effects of Ply on the initial macrophage inflammatory response to <jats:italic>S. pneumoniae<\/jats:italic>, and the consequences during early lung infection. We found that infection with <jats:italic>S. pneumoniae<\/jats:italic> expressing Ply suppressed tumour necrosis factor (TNF) and interleukin\u20106 production by MDMs compared to cells infected with <jats:italic>ply<\/jats:italic>\u2010deficient <jats:italic>S. pneumoniae<\/jats:italic>. This effect was independent of bacterial effects on cell death. Transcriptional analysis demonstrated <jats:italic>S. pneumoniae<\/jats:italic> expressing Ply caused a qualitatively similar but quantitatively lower MDM transcriptional response to <jats:italic>S. pneumoniae<\/jats:italic> compared to <jats:italic>ply<\/jats:italic>\u2010deficient <jats:italic>S. pneumoniae<\/jats:italic>, with reduced expression of TNF and type I IFN inducible genes. Reduction of the MDM inflammatory response was prevented by inhibition of SOCS1. In the early lung infection mouse model, the TNF response to <jats:italic>ply<\/jats:italic>\u2010deficient <jats:italic>S. pneumoniae<\/jats:italic> was enhanced and bacterial clearance increased compared to infection with wild\u2010type <jats:italic>S. pneumoniae<\/jats:italic>. Overall, these data show Ply inhibits the initial macrophage inflammatory response to <jats:italic>S. pneumoniae<\/jats:italic>, probably mediated through SOCS1, and this was associated with improved immune evasion during early lung infection.<\/jats:p>","DOI":"10.1111\/imm.13546","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T01:59:37Z","timestamp":1657850377000},"page":"413-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Pneumolysin suppresses the initial macrophage pro\u2010inflammatory response to <i>Streptococcus\u00a0pneumoniae<\/i>"],"prefix":"10.1111","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-3077","authenticated-orcid":false,"given":"Jimstan","family":"Periselneris","sequence":"first","affiliation":[{"name":"Centre for Inflammation and Tissue Repair, Division of Medicine University College Medical School  London 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