Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice

Abstract

Chlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll-like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-β in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3-/- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-β, IL-1β, and IL-6, but enhanced production of IL-10, TNF-α, and IFN-γ. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx.

TLR3 Deficiency Leads to Altered Immune Responses toChlamydia trachomatisInfection in Human Oviduct Epithelial Cells

“…Our research focuses on the impact of TLR3 signaling on the immune response to chlamydial infection in oviduct epithelium, and we were the first to demonstrate more severe genital tract pathogenesis in mice deficient in TLR3 confirming our hypothesis that TLR3 has a protective role in the immune responses to murine genital tract infections (32). In this investigation, our goal was to ascertain whether TLR3 had a similar protective role in the immune response to genital tract Chlamydia infection in humans and to more precisely delineate those immune responses in oviduct epithelial cells that contribute to the fibrosis and scarring that lead to reproductive sequelae in clinical disease.…”

“…In our previous investigations into the role of TLR3 in the pathogenesis of genital infections in mice, one key aspect of TLR3 deficiency that we observed was that mice deficient in TLR3 appeared exhibit indicators of more pronounced chronic sequelae, such as lymphocytic endometritis and hydrosalpinx (32). To examine whether TLR3 has a similar role in the pathogenesis of genital tract Chlamydia infections in humans, we next measured the Chlamydia -induced synthesis of biomarkers associated with chronic inflammatory disease and tissue necrosis in the WT and TLR3 deficient hOE cells.…”

“…We previously reported that murine OE cells showed dysregulation in the C. muridarum induced syntheses of a multitude of acute inflammatory mediators, and subsequently showed that TLR3 deficient mice exhibited increased chlamydial shedding, aberrant T-cell recruitment, and more severe genital tract pathology when compared to WT mice (15, 32). To assess whether the absence of TLR3 is associated with the chlamydial-induced syntheses of key biomarkers of inflammation in human oviduct epithelial cells, we performed multiplex ELISA analysis for the detection and quantification of key human innate-immune inflammatory biomarkers.…”

“…In our early investigations into the role of TLR3 in the immune response to genital tract Chlamydia infection, we showed that C. muridarum infected murine oviduct epithelial (OE) cells secrete IFN-β in a mostly TLR3 dependent manner, and that mouse OE cells deficient in TLR3 show dramatic reductions in the synthesis of other inflammatory immune mediators in addition to IFN-β (13, 15). Our most recent report shows that TLR3-deficient mice have increased chlamydial loads, aberrant genital tract secretion levels of several different inflammatory mediators, an altered CD4 + T-cell recruitment, and more severe oviduct and uterine horn pathology when compared to wild-type controls (32). Our data propose a protective role for TLR3 signaling in the immune response to Chlamydia infection in mice.…”

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“…Toll‐like receptor 4 (TLR4), a lipopolysaccharide receptor, might trigger the activation of the extracellular signaling pathway. Disorder of TLR4 contributed to the process of excessive release of inflammatory cytokines (Carrasco et al, ). In the network, there were two targets interacting with TLR4, which suggested that it is an important pathway for the treatment of PID.…”