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Infection and Immunity, September 2004, p. 5041-5051, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5041-5051.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Porphyromonas gingivalis Lipopolysaccharide Contains Multiple Lipid A Species That Functionally Interact with Both Toll-Like Receptors 2 and 4

Richard P. Darveau,1* Thu-Thao T. Pham,1 Kayde Lemley,2 Robert A. Reife,1 Brian W. Bainbridge,1 Stephen R. Coats,1 William N. Howald,3 Sing Sing Way,2 and Adeline M. Hajjar2

Departments of Periodontics,1 Immunology,2 Medicinal Chemistry, University of Washington, Seattle, Washington3

Received 12 March 2004/ Returned for modification 19 April 2004/ Accepted 26 May 2004

The innate host response to lipopolysaccharide (LPS) obtained from Porphyromonas gingivalis is unusual in that different studies have reported that it can be an agonist for Toll-like receptor 2 (TLR2) as well as an antagonist or agonist for TLR4. In this report it is shown that P. gingivalis LPS is highly heterogeneous, containing more lipid A species than previously described. In addition, purification of LPS can preferentially fractionate these lipid A species. It is shown that an LPS preparation enriched for lipid A species at m/z 1,435 and 1,450 activates human and mouse TLR2, TLR2 plus TLR1, and TLR4 in transiently transfected HEK 293 cells coexpressing membrane-associated CD14. The HEK cell experiments further demonstrated that cofactor MD-2 was required for functional engagement of TLR4 but not of TLR2 nor TLR2 plus TLR1. In addition, serum-soluble CD14 effectively transferred P. gingivalis LPS to TLR2 plus TLR1, but poorly to TLR4. Importantly, bone marrow cells obtained from TLR2–/– and TLR4–/– mice also responded to P. gingivalis LPS in a manor consistent with the HEK results, demonstrating that P. gingivalis LPS can utilize both TLR2 and TLR4. No response was observed from bone marrow cells obtained from TLR2 and TLR4 double-knockout mice, demonstrating that P. gingivalis LPS activation occurred exclusively through either TLR2 or TLR4. Although the biological significance of the different lipid A species found in P. gingivalis LPS preparations is not currently understood, it is proposed that the presence of multiple lipid A species contributes to cell activation through both TLR2 and TLR4.

* Corresponding author. Mailing address: Department of Periodontics, University of Washington, Health Sciences Center, Box 357444, Seattle, WA 98195. Phone: (206) 543-9514. Fax: (206) 616-7478. E-mail: rdarveau{at}u.washington.edu.

Editor: J. D. Clements

Infection and Immunity, September 2004, p. 5041-5051, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5041-5051.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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