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Infection and Immunity, June 2008, p. 2685-2695, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01625-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of Genes Particularly Sensitive to Lipopolysaccharide (LPS) in Human Monocytes Induced by Wild-Type versus LPS-Deficient Neisseria meningitidis Strains {triangledown}

Reidun Øvstebø,1* Ole Kristoffer Olstad,1 Berit Brusletto,1 Anne Sophie Møller,1 Audun Aase,3 Kari Bente Foss Haug,1 Petter Brandtzaeg,2,4 and Peter Kierulf1,4

Departments of Clinical Chemistry,1 Pediatrics, Ulleval University Hospital,2 Departments of Bacteriology and Immunology, The Norwegian Institute of Public Health,3 Faculty of Medicine, University of Oslo, Oslo, Norway4

Received 7 December 2007/ Returned for modification 25 January 2008/ Accepted 17 March 2008

Lipopolysaccharide (LPS) in the outer membrane of Neisseria meningitidis plays a dominant role as an inflammation-inducing molecule in meningococcal disease. We have used microarray analysis to study the global gene expression after exposure of human monocytes for 3 h to wild-type N. meningitidis (106), LPS-deficient N. meningitidis (106 and 108), and purified N. meningitidis LPS (1 ng [33 endotoxin units]/ml) to identify LPS-inducible genes. Wild-type N. meningitidis (106) induced 4,689 differentially expressed genes, compared with 72 differentially expressed genes induced by 106 LPS-deficient N. meningitidis organisms. However, 108 LPS-deficient N. meningitidis organisms induced 3,905 genes, indicating a dose-response behavior of non-LPS cell wall molecules. A comparison of the gene expression patterns from 106 wild-type N. meningitidis and 108 LPS-deficient N. meningitidis organisms showed that 2,401 genes in human monocytes were not strictly LPS dependent. A list of "particularly LPS-sensitive" genes (2,288), differentially induced by 106 wild-type N. meningitidis but not by 108 LPS-deficient N. meningitidis organisms, showed an early expression of beta interferon (IFN-β), most likely through the Toll-like receptor-MyD88-independent pathway. Subsequently, IFN-β may activate the type I IFN signaling pathway, and an unknown number of IFN-β-inducible genes, such as those for CXCL9, CXCL10, CXCL11, IFIT1, IFIT2, IFIT3, and IFIT5, are transcribed. Supporting this, human monocytes secreted significantly higher levels of CXCL10 and CXCL11 when stimulated by 106 wild-type N. meningitidis organisms than when stimulated by 108 LPS-deficient N. meningitidis organisms. Plasma CXCL10, but not CXCL11, was positively correlated (r = 0.67; P < 0.01) to LPS in patients (n = 24) with systemic meningococcal disease. Thus, new circulating biomarkers in meningococcal disease may be suggested through LPS-induced gene expression changes in human monocytes.

* Corresponding author. Mailing address: R&D Group, Department of Clinical Chemistry, Ullevål University Hospital 0407, Oslo, Norway. Phone: 47-22119490. Fax: 47-22118189. E-mail: reidun.ovstebo{at}medisin.uio.no

{triangledown} Published ahead of print on 24 March 2008.

Editor: J. N. Weiser

Infection and Immunity, June 2008, p. 2685-2695, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01625-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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