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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1574-1583.
Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-06-032961.
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Submitted June 30, 2006
Accepted September 25, 2006
Contribution of toll-like receptors to the innate immune response to gram-negative and gram-positive bacteria
Greg Elson*, Irene Dunn-Siegrist, Bruno Daubeuf, and Jerome Pugin
NovImmune S.A., Switzerland
University Hospital of Geneva, Switzerland
* Corresponding author; email: gelson{at}novimmune.com.
Innate recognition of bacteria is a key step in the activation of inflammation and coagulation, and is dependent on pathogen-associated molecular pattern (PAMP) ligation to Toll-like receptors (TLRs) and CD14. The dominant receptors activated when cells encounters a whole bacterium - which express several PAMPs - are poorly defined. Herein, we have stimulated various human cells with prototypic gram-negative and gram-positive bacteria. Receptor-dependent responses to whole bacteria were assessed using both TLR-transfected cells and specific monoclonal antibodies against TLRs, MD-2 and CD14. Enterobacteria activated leukocytes and endothelial cells in a TLR4/MD-2-dependent manner, most likely via lipopolysaccharide (LPS). TLR2 activation was observed with a high bacterial inoculum, and in epithelial cells expressing TLR2 but not TLR4. P. aeruginosa stimulated cells via both TLR2 and TLR4/MD-2. Gram-positive bacteria activated cells only at high concentrations, in a partially TLR2-dependent but TLR4/MD-2-independent manner. Either TLR or CD14 neutralization blocked activation to all bacterial strains tested with the exception of some gram-positive strains in whole blood where partial inhibition was noted. This study identifies dominant TLRs involved in responses to whole bacteria. It also validates the concept that host cell activation by bacterial pathogens can be therapeutically reduced by anti-TLR4, -TLR2 and -CD14 MAbs.
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