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Infection and Immunity, August 2008, p. 3717-3724, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00311-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses{triangledown}

Jeffrey M. Jordan,1 Michael E. Woods,1 Juan Olano,1,2 and David H. Walker1,2*

Department of Pathology,1 Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas 77555-06092

Received 9 March 2008/ Returned for modification 13 March 2008/ Accepted 9 May 2008

The importance of toll-like receptor 4 (TLR4) in immunity to rickettsiae remains elusive. To investigate the role of TLR4 in protection against rickettsioses, we utilized C3H/HeJ mice, which are naturally defective in TLR4 signaling, and compared the responses of C3H/HeN and C3H/HeJ mice following intravenous inoculation with Rickettsia conorii. Mice genetically defective in TLR4 signaling developed overwhelming, fatal rickettsial infections when given an inoculum that was nonfatal for TLR4-competent mice. In addition, mice lacking the ability to signal through TLR4 had significantly greater rickettsial burdens in vivo. Moreover, we observed greater concentrations of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha, IL-12p40, IL-12p70, and IL-17 in the sera of mice with intact TLR4 function as well as significantly greater quantities of activated CD4+ and CD8+ T lymphocytes. Additionally, we also observed that Th17 cells were present only in TLR4-competent mice, suggesting an important role for TLR4 ligation in the activation of this subset. In agreement with these data, we also observed significantly greater percentages of immunosuppressive regulatory T cells in the spleen during infection in TLR4-defective mice. Together, these data demonstrate that, while rickettsiae do not contain endotoxic lipopolysaccharide, they nevertheless initiate TLR4-specific immune responses, and these responses are important in protection.

* Corresponding author. Mailing address: Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0609. Phone: (409) 772-3989. Fax: (409) 772-1850. E-mail: dwalker{at}utmb.edu

{triangledown} Published ahead of print on 19 May 2008.

Editor: R. P. Morrison

Infection and Immunity, August 2008, p. 3717-3724, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00311-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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