Affiliation:
1. Departments of Clinical Chemistry
2. Departments of Bacteriology and Immunology, The Norwegian Institute of Public Health
3. Pediatrics, Ulleval University Hospital
4. Faculty of Medicine, University of Oslo, Oslo, Norway
Abstract
ABSTRACT
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
(10
6
), LPS-deficient
N. meningitidis
(10
6
and 10
8
), and purified
N. meningitidis
LPS (1 ng [33 endotoxin units]/ml) to identify LPS-inducible genes. Wild-type
N. meningitidis
(10
6
) induced 4,689 differentially expressed genes, compared with 72 differentially expressed genes induced by 10
6
LPS-deficient
N. meningitidis
organisms. However, 10
8
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 10
6
wild-type
N. meningitidis
and 10
8
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 10
6
wild-type
N. meningitidis
but not by 10
8
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 10
6
wild-type
N. meningitidis
organisms than when stimulated by 10
8
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
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