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-kappaB-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.
Subject(s)
Antigens, CD/immunology , Bronchi/immunology , Cell Adhesion Molecules/immunology , Moraxella catarrhalis/immunology , Neisseria meningitidis/immunology , Respiratory Mucosa/immunology , Toll-Like Receptor 2/immunology , Amino Acid Motifs/physiology , Antigens, Bacterial/immunology , Antigens, Bacterial/metabolism , Antigens, CD/chemistry , Bacterial Outer Membrane Proteins/immunology , Bacterial Outer Membrane Proteins/metabolism , Bronchi/metabolism , Bronchi/microbiology , Cell Adhesion Molecules/chemistry , Cells, Cultured , Cytokines/metabolism , Down-Regulation , Humans , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Respiratory Mucosa/metabolism , Respiratory Mucosa/microbiology , Signal Transduction/immunology , Toll-Like Receptor 2/metabolismABSTRACT
Moraxella catarrhalis is a major cause of exacerbations of chronic obstructive pulmonary disease (COPD) and emphysema. M. catarrhalis-specific UspA1 and the epithelial carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) were required to induce apoptosis. M. catarrhalis-induced apoptosis was significantly enhanced in HeLa cells stably transfected with CEACAM1, compared with HeLa cells not expressing CEACAM1. Infected cells showed increased activity of caspases 3, 6, and 9 but not of caspase 8. Reduced expression of Bcl-2, translocation of Bax into the mitochondria, and cytosolic increase of apoptosis-inducing factor in M. catarrhalis-infected cells implicated the involvement of mitochondrial death pathways. In conclusion, M. catarrhalis induced apoptosis in pulmonary epithelial cells--a process that was triggered by interaction between CEACAM1 and UspA1. Thus, M. catarrhalis-induced apoptosis of pulmonary epithelial cells may contribute to the development of COPD and emphysema.
