The absence of Toll-like receptor 4 signaling in C3H/HeJ mice predisposes them to overwhelming rickettsial infection and decreased protective Th1 responses

Infect Immun. 2008 Aug;76(8):3717-24. doi: 10.1128/IAI.00311-08. Epub 2008 May 19.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Boutonneuse Fever / immunology*
  • Brain / microbiology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Colony Count, Microbial
  • Cytokines / blood
  • Disease Susceptibility*
  • Lethal Dose 50
  • Lung / microbiology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Rickettsia conorii / immunology*
  • Spleen / immunology
  • Survival Analysis
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / immunology*
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / immunology*


  • Cytokines
  • Toll-Like Receptor 4