Abstract
Although Moraxella catarrhalis and Neisseria meningitidis are important human pathogens, they often colonize the human respiratory tract without causing overt clinical symptoms. Both pathogens express structurally unrelated proteins that share the ability to stimulate the adhesion molecule CEACAM1 expressed on human cells. Here we demonstrate that the interaction of CEACAM1 with ubiquitous surface protein A1 expressed on M. catarrhalis or with opacity-associated proteins on N. meningitidis resulted in reduced Toll-like receptor 2–initiated transcription factor NF-κB–dependent inflammatory responses of primary pulmonary epithelial cells. These inhibitory effects were mediated by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif of CEACAM1 and by recruitment of the phosphatase SHP-1, which negatively regulated Toll-like receptor 2–dependent activation of the phosphatidylinositol 3-OH kinase–Akt kinase pathway. Our results identify a CEACAM1-dependent immune-evasion strategy.
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Acknowledgements
We thank J. Hellwig, F. Schreiber, A. Kuehn and M. Brant for technical assistance; J. Lippman for support in confirming the siRNA experiments; E. Hansen (University of Texas Southwestern Medical Center) for O35E and O35E.1; P. van der Ley (Laboratory of Vaccine Research, National Institute of Public Health and the Environment) for the parental E. coli strain PC2984 and the Opa J129– and Opa B128–expressing strains; C. Kirschning (Technical University Munich) for the pFlag-CMV-TLR2 expression plasmids; and H. Heine (Research Center Borstel) for GFP-tagged TLR2 plasmids. Supported by Deutsche Forschungsgemeinschaft (SL 153/1-1 to H.S. and OP 86/5-1 to B.O.), the Swedish Medical Research Council (K.R.) and Bundesministerium für Bildung und Forschung (project 13 of the German Chronic Obstructive Pulmonary Disease and Systemic Consequences-Comorbidities Network to H.S. and project B3 of the Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis to N.S.).
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H.S. planned the project; H.S. and B.B.S. designed and directed the experiments; B.B.S., S.Z. and H.S. did signaling analysis with immunoprecipitation, immunoblot analysis and ELISA; B.B.S. generated, characterized, produced and purified monoclonal antibody 18/20; A.H. did and analyzed the confocal laser-scanning microscopy; B.O., J.E. and S.Z. did the siRNA and overexpression experiments; B.O., P.D.N'G. and J.Z. provided advice for the experiments and analyzed data; B.B.S. and J.Z. did flow cytometry; W.Z. generated the CEACAM1 expression plasmids; K.R. produced recombinant UspA1; W.Z. and K.R. edited the manuscript; B.T.-W. isolated and characterized the PBECs; N.S. and L.L. supervised the research and contributed to manuscript criticism; and H.S. and B.B.S. wrote the manuscript.
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Slevogt, H., Zabel, S., Opitz, B. et al. CEACAM1 inhibits Toll-like receptor 2–triggered antibacterial responses of human pulmonary epithelial cells. Nat Immunol 9, 1270–1278 (2008). https://doi.org/10.1038/ni.1661
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DOI: https://doi.org/10.1038/ni.1661
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