The lipid A phosphate position determines differential host Toll-like receptor 4 responses to phylogenetically related symbiotic and pathogenic bacteria.
The human symbiont Bacteroides thetaiotaomicron promotes intestinal function and health, whereas the phylogenetically related pathogen Porphyromonas gingivalis is associated with the chronic oral inflammatory disease periodontitis. Although both B. thetaiotaomicron and P. gingivalis synthesize lipopolysaccharides (LPS) consisting of penta-acylated, monophosphorylated lipid A in addition to immunologically silent, nonphosphorylated lipid A, they elicit strikingly distinct Toll-like receptor 4 (TLR4) responses. We show that the phosphate position of penta-acylated, monophosphorylated lipid A is a key feature for determining the differential TLR4 responses elicited by these evolutionarily related bacteria. B. thetaiotaomicron produces TLR4-stimulatory lipid A bearing a 1-phosphate, in contrast to P. gingivalis, which produces TLR4-evasive lipid A bearing a 4'-phosphate. Confirming these observations, recombinant Escherichia coli LPS containing penta-acylated, 1-phosphorylated lipid A is more TLR4 stimulatory than LPS containing 4'-phosphorylated lipid A. The specific capacity of a Gram-negative bacterium to alert or evade the host innate immune defense system through TLR4-dependent signaling is currently recognized as a critical aspect defining the relationship between the host and the bacterium. We propose that the distinct lipid A phosphate positions observed for the B. thetaiotaomicron and P. gingivalis LPS contributes to the manifestation of these bacteria as commensal or pathogen within the human host.
Coats
Stephen R
SR
Department of Periodontics, School of Dentistry, University of Washington, 1959 NE Pacific St., HSB, Box 357444, Seattle, WA 98195, USA. scoats@u.washington.edu
Berezow
Alex B
AB
To
Thao T
TT
Jain
Sumita
S
Bainbridge
Brian W
BW
Banani
Karim P
KP
Darveau
Richard P
RP
D001439:Bacteroides / Q000235:genetics* / Q000378:metabolism; D002236:Carbohydrate Conformation; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008050:Lipid A / Q000737:chemistry* / Q000378:metabolism; D010802:Phylogeny; D016966:Porphyromonas gingivalis / Q000235:genetics* / Q000378:metabolism; D013559:Symbiosis; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4