title: Ehrlichia chaffeensis downregulates surface Toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-kappa B, ERK 1/2 and p38 MAPK in host monocytes.
abstract: Microbial ligands, such as lipopolysaccharide (LPS), activate Toll-like receptors (TLRs) of mononuclear phagocytes, thus activating transcription factors including NF-kappa B and inducing antimicrobial activity. Ehrlichia chaffeensis, an obligatory intramonocytic Gram-negative bacterium, causes human monocytic ehrlichiosis. In the present study, we found that E. chaffeensis-infected human monocytes became progressively less responsive to Escherichia coli lipopolysaccharide (LPS) in activating NF-kappa B and mobilizing ehrlichiacidal activities. E. chaffeensis infection caused downregulation of the expression of several pattern recognition receptors, such as CD14, TLR2 and TLR4, as revealed by flow cytometry and/or reverse transcription polymerase chain reaction analysis. Electrophoretic mobility shift assay revealed that the activity of a transcription factor PU.1 was also downregulated by E. chaffeensis infection. ERK 1/2 and p38 MAPK were slightly activated at the early stage of E. chaffeensis infection; however, the activations of ERK 1/2 and p38 MAPK by LPS treatment were subsequently reduced in E. chaffeensis-infected monocytes compared with those in uninfected monocytes. Like E. chaffeensis, the p38 MAPK-specific inhibitor SB 203580 downregulated PU.1 activity and the expression of TLR2, TLR4 and CD14 in human monocytes, suggesting that the inhibition of p38 MAPK by E. chaffeensis is involved in the suppression of several downstream signalling pathways. These data point to a novel mechanism by which E. chaffeensis can survive by inhibiting critical signalling in monocyte activation pathways linked to pattern recognition receptors.
authors.affiliation: Department of Veterinary Biosciences, 1925 Coffey Road, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Mingqun
authors.initials: M
authors.lastname: Lin
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Rikihisa
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D018469:Ehrlichia chaffeensis / Q000472:pathogenicity*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1; C495342:TLR2 protein, human; C495345:TLR4 protein, human