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Pneumolysin suppresses the initial macrophage pro-inflammatory response to Streptococcus pneumoniae infection

Periselneris, Jimstan; Turner, Carolin T; Ercoli, Giuseppe; Szylar, Gabriella; Weight, Caroline M; Thurston, Teresa; Whelan, Matthew; ... Brown, Jeremy; + view all (2022) Pneumolysin suppresses the initial macrophage pro-inflammatory response to Streptococcus pneumoniae infection. Immunology 10.1111/imm.13546. (In press).

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Abstract

Background: Published data for the Streptococcus pneumoniae virulence factor Pneumolysin (Ply) show contradictory effects on the host inflammatory response to infection. Ply has been shown to activate the inflammasome, but also can bind to MRC-1 resulting in suppression of dendritic cell inflammatory responses. Methods: We have used an in vitro infection model of human monocyte derived macrophages (MDM), and a mouse model of pneumonia to clarify whether pro- or anti-inflammatory effects dominate the effects of Ply on the initial macrophage inflammatory response to S. pneumoniae, and the consequences during early lung infection. Results: We found that infection with S. pneumoniae expressing Ply suppressed TNF and IL6 production by MDMs compared to cells infected with ply-deficient S. pneumoniae. This effect was independent of bacterial effects on cell death. Transcriptional analysis demonstrated S. pneumoniae expressing Ply caused a qualitatively similar but quantitatively lower MDM transcriptional response to S. pneumoniae compared to ply-deficient S. pneumoniae, 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 ply-deficient S. pneumoniae was enhanced and bacterial clearance increased compared to infection with wild type S. pneumoniae. Conclusion: Overall, these data show Ply inhibits the initial macrophage inflammatory response to S. pneumoniae, probably mediated through SOCS1, and this was associated with improved immune evasion during early lung infection.

Type: Article
Title: Pneumolysin suppresses the initial macrophage pro-inflammatory response to Streptococcus pneumoniae infection
Location: England
DOI: 10.1111/imm.13546
Publisher version: https://doi.org/10.1111/imm.13546
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Streptococcus pneumoniae, epithelial immunity, inflammation, pneumolysin
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10152440
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