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Infection and Immunity, December 2006, p. 6730-6738, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00934-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Lack of In Vitro and In Vivo Recognition of Francisella tularensis Subspecies Lipopolysaccharide by Toll-Like Receptors{triangledown}

Adeline M. Hajjar,1 Megan D. Harvey,2 Scott A. Shaffer,3 David R. Goodlett,3 Anders Sjöstedt,6 Helen Edebro,6 Mats Forsman,7 Mona Byström,7 Mark Pelletier,2 Christopher B. Wilson,1 Samuel I. Miller,2,4,5 Shawn J. Skerrett,2 and Robert K. Ernst2*

Departments of Immunology,1 Medicine,2 Medicinal Chemistry,3 Microbiology,4 Genome Sciences, University of Washington, Seattle, Washington,5 Department of Clinical Microbiology, Clinical Bacteriology, Umeå University, Umeå, Sweden,6 Department of NBC-Analysis, Swedish Defence Research Agency, Umeå, Sweden7

Received 12 June 2006/ Returned for modification 4 August 2006/ Accepted 1 September 2006

Francisella tularensis is an intracellular gram-negative bacterium that is highly infectious and potentially lethal. Several subspecies exist of varying pathogenicity. Infection by only a few organisms is sufficient to cause disease depending on the model system. Lipopolysaccharide (LPS) of gram-negative bacteria is generally recognized by Toll-like receptor 4 (TLR4)/MD-2 and induces a strong proinflammatory response. Examination of human clinical F. tularensis isolates revealed that human virulent type A and type B strains produced lipid A of similar structure to the nonhuman model pathogen of mice, Francisella novicida. F. novicida LPS or lipid A is neither stimulatory nor an antagonist for human and murine cells through TLR4 or TLR2. It does not appear to interact with TLR4 or MD-2, as it is not an antagonist to other stimulatory LPS. Consistent with these observations, aerosolization of F. novicida LPS or whole bacteria induced no inflammatory response in mice. These results suggest that poor innate recognition of F. tularensis allows the bacterium to evade early recognition by the host innate immune system to promote its pathogenesis for mammals.

* Corresponding author. Mailing address: Department of Medicine, University of Washington, Health Sciences Building, Box 357710, 1959 NE Pacific St., Seattle, WA 98195. Phone: (206) 616-4028. Fax: (206) 543-5383. E-mail: rkernst{at}u.washington.edu.

{triangledown} Published ahead of print on 18 September 2006.

Editor: J. N. Weiser

Infection and Immunity, December 2006, p. 6730-6738, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00934-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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