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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Surface / physiology
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Biological Factors / metabolism
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CHO Cells
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Carrier Proteins / genetics
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Carrier Proteins / physiology
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Cells, Cultured
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Cricetinae
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Drosophila Proteins*
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Humans
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Inflammation Mediators / metabolism
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Lipopolysaccharide Receptors / metabolism*
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Lymphocyte Antigen 96
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Macrophages / immunology*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / physiology
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Mice
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Mice, Knockout
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Models, Immunological
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, Cell Surface / physiology
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Receptors, Interleukin-1*
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Sepsis / immunology
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Streptococcal Infections / immunology
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Streptococcus agalactiae / physiology*
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Toll-Like Receptor 1
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptor 6
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Toll-Like Receptors
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Transfection
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Antigens, Surface
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Biological Factors
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Carrier Proteins
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Drosophila Proteins
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Inflammation Mediators
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LY96 protein, human
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Lipopolysaccharide Receptors
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Lymphocyte Antigen 96
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Membrane Glycoproteins
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Receptors, Cell Surface
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Receptors, Interleukin-1
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TIRAP protein, human
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TIRAP protein, mouse
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TLR2 protein, human
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TLR4 protein, human
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TLR6 protein, human
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Tlr6 protein, mouse
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Toll-Like Receptor 1
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptor 6
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha