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  1. J. Nichols1,
  2. J. Sikes1,
  3. C. W. Andrews Jr2,
  4. D. M. Ojcius3,
  5. T. Darville1
  1. 1University of Arkansas for Medical Sciences, Little Rock, AR
  2. 2Rockdale, Atlanta, GA
  3. 3University of California, Merced, CA


Chlamydia trachomatis ligands are known to stimulate both TLR2 and TLR4. Our prior studies of chlamydial genital tract infection in the mouse model have revealed that the development of pathology is dependent on intact TLR2-mediated responses; however, in the absence of TLR2, normal resolution of infection occurred. Normal resolution of infection was also seen in mice deficient for TLR4. This suggests that the generation of a normal adaptive immune response to chlamydial infection may occur via multiple alternative or complementary pathogen recognition receptor (PRR) pathways.

Purpose Our current studies were undertaken to examine the potential redundancy in the TLR2 and TLR4 pathways for the generation of adaptive immunity to chlamydial infection.

Methods We examined the course of primary chlamydial infection in wild-type, MyD88 KO, TLR2/TLR4 double-knockout (DKO) and TLR4/MyD88 DKO mice after intravaginal inoculation. We evaluated cytokines, T-cell responses, and antibody responses after infection.

Summary of Results The course of infection in TLR2/TLR4 DKO was similar to that of wild-type mice, with a moderate reduction in cytokine responses. In contrast, in both MyD88 KO and TLR4/MyD88 DKO mice, resolution of infection was significantly delayed with delayed or absent proinflammatory cytokine responses. In vitro proliferation of antigen-stimulated iliac node CD4 T cells was equal in wild-type and MyD88 KO mice but absent in TLR4/MyD88 DKOs. Chlamydia-specific antibody responses in MyD88 KO, TLR2/TLR4, and TLR4/MyD88 DKO mice were equal to wild-type responses.

Conclusions Normal resolution infection in TLR2/TLR4 DKOs suggests that alternative PRR pathways drive the response that promotes clearance of infection. Our findings also demonstrate that there is a TLR4-dependent/MyD88-independent pathway, likely the TLR4-Trif pathway, that can drive CD4 T-cell proliferation in response to chlamydial infection. However, this response is not necessary for infection clearance, given the ability of TLR4/MyD88 DKO to resolve infection. An intact antibody response, shown here to be independent of TLR4, TLR2, and MyD88 pathways, is adequate to resolve chlamydial infection in the presence of innate immune cells despite an absence of CD4 T-cell activation.

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