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    Novel engagement of CD14 and multiple toll-like receptors by group B streptococci

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    Authors
    Henneke, Phillip
    Takeuchi, Osamu
    van Strijp, Jos A.
    Guttormsen, Hilde-Kari
    Smith, Jason A.
    Schromm, Andra B.
    Espevik, Terje
    Akira, Shizuo
    Nizet, Victor
    Kasper, Dennis L.
    Golenbock, Douglas
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    UMass Chan Affiliations
    Department of Medicine, Division of Infectious Diseases and Immunology
    Document Type
    Journal Article
    Publication Date
    2001-12-12
    Keywords
    Animals
    Antigens, CD14
    Antigens, Surface
    Biological Factors
    CHO Cells
    Carrier Proteins
    Cells, Cultured
    Cricetinae
    *Drosophila Proteins
    Humans
    Inflammation Mediators
    Lymphocyte Antigen 96
    Macrophages
    Membrane Glycoproteins
    Mice
    Mice, Knockout
    Models, Immunological
    Receptors, Cell Surface
    *Receptors, Interleukin-1
    Sepsis
    Streptococcal Infections
    Streptococcus agalactiae
    Toll-Like Receptor 1
    Toll-Like Receptor 2
    Toll-Like Receptor 4
    Toll-Like Receptor 6
    Toll-Like Receptors
    Transfection
    Tumor Necrosis Factor-alpha
    Life Sciences
    Medicine and Health Sciences
    Show allShow less
    
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    Link to Full Text
    https://doi.org/10.4049/jimmunol.167.12.7069
    Abstract
    Group B streptococcus (GBS) imposes a major health threat to newborn infants. Little is known about the molecular basis of GBS-induced sepsis. Both heat-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-kappaB, the secretion of TNF-alpha, and the formation of NO in mouse macrophages. Macrophages from mice with a targeted disruption of MyD88 failed to secrete TNF-alpha in response to both heat-inactivated whole bacteria and GBS-F, suggesting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoundly from that by secreted GBS-F. Whole GBS activated macrophages independently of TLR2 and TLR6, whereas a response to the secreted GBS-F was not observed in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TLR4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular polysaccharide or beta-hemolysin had GBS-F activity comparable to that of wild-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as coreceptors for secreted microbial products derived from GBS and that cell wall components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.
    Source

    J Immunol. 2001 Dec 15;167(12):7069-76.

    DOI
    10.4049/jimmunol.167.12.7069
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/38250
    PubMed ID
    11739528
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    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.167.12.7069
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      Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction

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      The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.
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