The absence of Toll-like receptor 4 signaling in C3H/HeJ mice predisposes them to overwhelming rickettsial infection and decreased protective Th1 responses.
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.
Jordan
Jeffrey M
JM
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0609, USA.
Woods
Michael E
ME
Olano
Juan
J
Walker
David H
DH
D000818:Animals; D001907:Boutonneuse Fever / Q000276:immunology*; D001921:Brain / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015169:Colony Count, Microbial; D016207:Cytokines / Q000097:blood; D004198:Disease Susceptibility; D007928:Lethal Dose 50; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020114:Rickettsia conorii / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*
D016207:Cytokines; D051197:Toll-Like Receptor 4