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TLR-Mediated Inflammatory Responses to Streptococcus pneumoniae are Highly Dependent on Surface Expression of Bacterial Lipoproteins

Lookup NU author(s): Christine Aldridge, Professor Waldemar Vollmer



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 Delta 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-kappa B activation and TNF-alpha release were reduced in response to the Delta lgt strain. Differences in TNF-alpha responses between Delta lgt 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 Delta lgt S. pneumoniae, comprising many NF-kappa B-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.

Publication metadata

Author(s): Tomlinson G, Chimalapati S, Pollard T, Lapp T, Cohen J, Camberlein E, Stafford S, Periselneris J, Aldridge C, Vollmer W, Picard C, Casanova JL, Noursadeghi M, Brown J

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2014

Volume: 193

Issue: 7

Pages: 3736-3745

Print publication date: 01/10/2014

Online publication date: 29/08/2014

Acceptance date: 04/08/2014

Date deposited: 26/11/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists


DOI: 10.4049/jimmunol.1401413


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Funder referenceFunder name
University College London Hospitals charities
Department of Health's National Institute for Health Research Biomedical Research Centre
Rosetrees Trust
BB/G015902/1Biotechnology and Biological Sciences Research Council
G0700569Medical Research Council
G0600410Medical Research Council
G0700829Medical Research Council
G0801211Medical Research Council
MR/K00168X/1Medical Research Council
WT077161Wellcome Trust
WT076442Wellcome Trust