Open AccessHuman Toll‐like receptor 4 responses to P. gingivalis are regulated by lipid A 1‐ and 4′‐phosphatase activities
Author(s) -
Coats Stephen R.,
Jones Jace W.,
Do Christopher T.,
Braham Pamela H.,
Bainbridge Brian W.,
To Thao T.,
Goodlett David R.,
Ernst Robert K.,
Darveau Richard P.
Publication year - 2009
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2009.01349.x
Subject(s) - innate immune system , biology , porphyromonas gingivalis , lipid a , tlr4 , toll like receptor , lipopolysaccharide , dephosphorylation , phosphatase , receptor , immune system , pattern recognition receptor , microbiology and biotechnology , tlr2 , pathogen , signal transduction , phosphorylation , bacteria , biochemistry , immunology , genetics
Summary 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.