Abstract
Enterobacter sakazakii (ES) is an emerging pathogen that causes meningitis and necrotizing enterocolitis in infants. Dendritic cells (DCs) are professional phagocytic cells that play an essential role in host defense against invading pathogens; however, the interaction of ES with DCs is not known. In this study, we demonstrate that ES targets DC-specific ICAM nonintegrin (DC-SIGN) to survive in myeloid DCs for which outer membrane protein A (OmpA) expression in ES is critical, although it is not required for uptake. In addition, DC-SIGN expression was sufficient to cause a significant invasion by ES in HeLa cells and intestinal epithelial cells, which are normally not invaded by ES. OmpA(+) ES prevented the maturation of DCs by triggering the production of high levels of IL-10 and TGF-beta and by suppressing the activation of MAPKs. Pretreatment of DCs with Abs to IL-10 and TGF-beta or of bacteria with anti-OmpA Abs significantly enhanced the maturation markers on DCs. Furthermore, DCs pretreated with various inhibitors of MAPKs prohibited the increased production of proinflammatory cytokines stimulated by LPS or OmpA(-) ES. LPS pretreatment followed by OmpA(+) ES infection of DCs failed to induce maturation of DCs, indicating that OmpA(+) ES renders the cells in immunosuppressive state to external stimuli. Similarly, OmpA(+) ES-infected DCs failed to present Ag to T cells as indicated by the inability of T cells to proliferate in MLR. We conclude that ES interacts with DC-SIGN to subvert the host immune responses by disarming MAPK pathway in DCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anthracenes / pharmacology
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Bacterial Outer Membrane Proteins / genetics
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Bacterial Outer Membrane Proteins / immunology*
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Bacterial Outer Membrane Proteins / metabolism
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Butadienes / pharmacology
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Cell Adhesion Molecules / immunology*
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Cell Adhesion Molecules / metabolism
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Cell Survival / drug effects
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Cell Survival / immunology
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Cronobacter sakazakii / immunology*
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Cronobacter sakazakii / ultrastructure
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / microbiology
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Enterobacteriaceae Infections / immunology*
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Epithelial Cells / microbiology
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Flavonoids / pharmacology
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HeLa Cells
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Humans
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Imidazoles / pharmacology
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Microscopy, Electron, Scanning
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Microscopy, Electron, Transmission
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Nitriles / pharmacology
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Pyridines / pharmacology
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Rats
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Transfection
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
Substances
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Anthracenes
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Bacterial Outer Membrane Proteins
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Butadienes
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Lectins, C-Type
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Lipopolysaccharides
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Nitriles
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Pyridines
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Receptors, Cell Surface
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Transforming Growth Factor beta
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U 0126
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Interleukin-10
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OMPA outer membrane proteins
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pyrazolanthrone
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Mitogen-Activated Protein Kinase Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one