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Infection and Immunity, November 2004, p. 6446-6454, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6446-6454.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Intact Gram-Negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus Bacteria Activate Innate Immunity via Toll-Like Receptor 2 but Not Toll-Like Receptor 4

Leisa Mandell,1 Anthony P. Moran,2 Andrew Cocchiarella,1 JeanMarie Houghton,1,3 Nancy Taylor,4 James G. Fox,4 Timothy C. Wang,1,3 and Evelyn A. Kurt-Jones1*

Division of Gastroenterology,3 Department of Medicine, University of Massachusetts Medical Center, Worcester,1 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts,4 Department of Microbiology, National University of Ireland, Galway, Ireland2

Received 3 March 2004/ Returned for modification 5 April 2004/ Accepted 20 May 2004

Molecular and genetic studies have demonstrated that members of the Toll-like receptor (TLR) family are critical innate immune receptors. TLRs are recognition receptors for a diverse group of microbial ligands including bacteria, fungi, and viruses. This study demonstrates that distinct TLRs are responsible for the recognition of Helicobacter lipopolysaccharide (LPS) versus intact Helicobacter bacteria. We show that the cytokine-inducing activity of Helicobacter LPS was mediated by TLR4; i.e., TLR4-deficient macrophages were unresponsive to Helicobacter pylori LPS. Surprisingly, the cytokine response to whole Helicobacter bacteria (H. pylori, H. hepaticus, and H. felis) was mediated not by TLR4 but rather by TLR2. Studies of HEK293 transfectants revealed that expression of human TLR2 was sufficient to confer responsiveness to intact Helicobacter bacteria, but TLR4 transfection was not sufficient. Our studies further suggest that cag pathogenicity island genes may modulate the TLR2 agonist activity of H. pylori as cagA+ bacteria were more active on a per-cell basis compared to cagA mutant bacteria for interleukin-8 (IL-8) cytokine secretion. Consistent with the transfection studies, analysis of knockout mice demonstrated that TLR2 was required for the cytokine response to intact Helicobacter bacteria. Macrophages from both wild-type and TLR4-deficient mice produced a robust cytokine secretion response (IL-6 and MCP-1) when stimulated with intact Helicobacter bacteria. In contrast, macrophages from TLR2-deficient mice were profoundly unresponsive to intact Helicobacter stimulation, failing to secrete cytokines even at high (100:1) bacterium-to-macrophage ratios. Our studies suggest that TLR2 may be the dominant innate immune receptor for recognition of gastrointestinal Helicobacter species.

* Corresponding author. Mailing address: University of Massachusetts Medical Center, 364 Plantation St., Lazare Research Building Rm. 226, Worcester, MA 01605. Phone: (508) 856-3531. Fax: (508) 856-6176. E-mail: Evelyn.Kurt-Jones{at}umassmed.edu.

Editor: F. C. Fang

Infection and Immunity, November 2004, p. 6446-6454, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6446-6454.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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