期刊
JOURNAL OF IMMUNOLOGY
卷 193, 期 7, 页码 3736-3745出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1401413
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资金
- Department of Health's National Institute for Health Research Biomedical Research Centre
- Medical Research Council [G0700569, G0700829, G0600410, MR/K00168X/1, G0801211]
- Wellcome Trust [WT076442, WT077161]
- University College London Hospitals charities
- Rosetrees Trust
- Biotechnology and Biological Sciences Research Council [BB/G015902/1]
- BBSRC [BB/G015902/1] Funding Source: UKRI
- MRC [G0700569, G0801211, G0700829, MR/K00168X/1, G0600410] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL5-Cohen] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/G015902/1] Funding Source: researchfish
- Medical Research Council [G0700569, G0600410, G0801211, G0700829, MR/K00168X/1] Funding Source: researchfish
- National Institute for Health Research [CL-2009-18-010, CL-2012-18-007] Funding Source: researchfish
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.
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