|
|||||
|
|
Human Toll-like receptor 4 responses to P. gingivalis are regulated by lipid A 1- and 4'-phosphatase activities |
|
| Authors: | Stephen R Coats Jace W Jones Christopher T Do Pamela H Braham Brian W Bainbridge Thao T To David R Goodlett Robert K Ernst Richard P Darveau |
| Institution: | Departments of Periodontics and;Oral Biology, School of Dentistry, University of Washington, 1959 NE Pacific St., Seattle, WA 98195-7444, USA.; Departments of Chemistry and;Medicinal Chemistry, University of Washington, 1959 NE Pacific St., Seattle, WA 98195-1700, USA.; Department of Microbial Pathogenesis, University of Maryland-Baltimore, 650 W. Baltimore St. 8 South, Baltimore, MD 21201, USA. |
| Abstract: | 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. |
| Keywords: | |