Toll-Like Receptor-2, but Not Toll-Like Receptor-4, Is Essential for Development of Oviduct Pathology in Chlamydial Genital Tract Infection

Abstract

The roles of Toll-like receptor (TLR) 2 and TLR4 in the host inflammatory response to infection caused by Chlamydia trachomatis have not been elucidated. We examined production of TNF-α and IL-6 in wild-type TLR2 knockout (KO), and TLR4 KO murine peritoneal macrophages infected with the mouse pneumonitis strain of C. trachomatis. Furthermore, we compared the outcomes of genital tract infection in control, TLR2 KO, and TLR4 KO mice. Macrophages lacking TLR2 produced significantly less TNF-α and IL6 in response to active infection. In contrast, macrophages from TLR4 KO mice consistently produced higher TNF-α and IL-6 responses than those from normal mice on in vitro infection. Infected TLR2-deficient fibroblasts had less mRNA for IL-1, IL-6, and macrophage-inflammatory protein-2, but TLR4-deficient cells had increased mRNA levels for these cytokines compared with controls, suggesting that ligation of TLR4 by whole chlamydiae may down-modulate signaling by other TLRs. In TLR2 KO mice, although the course of genital tract infection was not different from that of controls, significantly lower levels of TNF-α and macrophage-inflammatory protein-2 were detected in genital tract secretions during the first week of infection, and there was a significant reduction in oviduct and mesosalpinx pathology at late time points. TLR4 KO mice responded to in vivo infection similarly to wild-type controls and developed similar pathology. TLR2 is an important mediator in the innate immune response to C. trachomatis infection and appears to play a role in both early production of inflammatory mediators and development of chronic inflammatory pathology.

Immune-mediated control of Chlamydia infection

“…On the other hand, there is evidence that these inflammatory cytokines may also contribute to the pathology associated with Chlamydia infection. For example, lower levels of TNF-a and IL-6 have been correlated with decreased genital tract tissue pathology following Chlamydia genital infection (Darville et al, 2003).…”

Chlamydial Intracellular Survival Strategies

“…TLR2 appears to be the predominant receptor required for an inflammatory response to infection (Prebeck et al 2001;Darville et al 2003;O'Connell et al 2006). Interestingly, TLR2 and its adaptor MyD88 localize to the periphery of the chlamydial inclusion during active infection, suggesting that TLR2 may signal intracellularly during infection (Mackern-Oberti et al 2006;O'Connell et al 2006).…”

Mice Deficient in MyD88 Develop a Th2-Dominant Response and Severe Pathology in the Upper Genital Tract following Chlamydia muridarum Infection

“…Third, both TLRs and MyD88 can be recruited to the inclusion in the infected cells (36,37). Finally, mice deficient in TLR2 cleared infection as efficiently as wild-type mice but developed less pathology in the oviduct than the wild-type mice (38), whereas there was a slight increase in recovery of live organisms from vaginal samples of MyD88 KO mice (35). The remaining questions are: can MyD88 deficiency lead to enhanced ascending infection to the upper genital tract?…”