Tomlinson, G;
Chimalapati, S;
Pollard, T;
Lapp, T;
Cohen, J;
Camberlein, E;
Stafford, S;
... Brown, J; + view all
(2014)
TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.
J Immunol
, 193
(7)
pp. 3736-3745.
10.4049/jimmunol.1401413.
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Abstract
Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host-pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB-regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2-associated responses were preserved. Experiments using leukocytes from IL-1R-associated kinase-4-deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R-associated kinase-4-mediated inflammatory responses to S. pneumoniae.
| Type: | Article |
|---|---|
| Title: | TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.4049/jimmunol.1401413 |
| Publisher version: | http://dx.doi.org/10.4049/jimmunol.1401413 |
| Additional information: | © 2014 The Authors. This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license. |
| Keywords: | Animals, Bacterial Proteins, Disease Models, Animal, Female, Gene Expression Regulation, Bacterial, HEK293 Cells, Humans, Immunologic Deficiency Syndromes, Interleukin-1 Receptor-Associated Kinases, Lipoproteins, Macrophages, Male, Mice, Mice, Knockout, NF-kappa B, Pneumonia, Pneumococcal, Streptococcus pneumoniae, Toll-Like Receptor 2, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 Infection and Immunity 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 Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1447788 |
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