Human Toll-like receptor 4 responses to P. gingivalis are regulated by lipid A 1- and 4'-phosphatase activities.
Signal transduction following binding of lipopolysaccharide (LPS) to Toll-like receptor 4 (TLR4) is an essential aspect of host innate immune responses to infection by Gram-negative pathogens. Here, we describe a novel molecular mechanism used by a prevalent human bacterial pathogen to evade and subvert the human innate immune system. We show that the oral pathogen, Porphyromonas gingivalis, uses endogenous lipid A 1- and 4'-phosphatase activities to modify its LPS, creating immunologically silent, non-phosphorylated lipid A. This unique lipid A provides a highly effective mechanism employed by this bacterium to evade TLR4 sensing and to resist killing by cationic antimicrobial peptides. In addition, lipid A 1-phosphatase activity is suppressed by haemin, an important nutrient in the oral cavity. Specifically, P. gingivalis grown in the presence of high haemin produces lipid A that acts as a potent TLR4 antagonist. These results suggest that haemin-dependent regulation of lipid A 1-dephosphorylation can shift P. gingivalis lipid A activity from TLR4 evasive to TLR4 suppressive, potentially altering critical interactions between this bacterium, the local microbial community and the host innate immune system.
Coats
Stephen R
SR
Department of Periodontics, School of Dentistry, University of Washington, 1959 NE Pacific St., Seattle, WA 98195-7444, USA. scoats@u.washington.edu
Jones
Jace W
JW
Do
Christopher T
CT
Braham
Pamela H
PH
Bainbridge
Brian W
BW
To
Thao T
TT
Goodlett
David R
DR
Ernst
Robert K
RK
Darveau
Richard P
RP
D001426:Bacterial Proteins / Q000378:metabolism*; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000276:immunology; D006427:Hemin / Q000276:immunology; D006801:Humans; D008050:Lipid A / Q000276:immunology* / Q000378:metabolism*; D050296:Microbial Viability; D008954:Models, Biological; D016328:NF-kappa B / Q000276:immunology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000276:immunology* / Q000472:pathogenicity*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D037521:Virulence Factors / Q000378:metabolism*
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008050:Lipid A; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D037521:Virulence Factors; D006427:Hemin; C546357:lipid A 1-phosphatase, Porphyromonas gingivalis; C095015:lipid A 4'-phosphatase; D010744:Phosphoric Monoester Hydrolases