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

Sebastian E Carrasco,Denise M Imai,X Frank Yang,George E Sandusky,Ramesh Kumar,Wilbert A Derbigny,Sishun Hu

doi:10.1371/journal.pone.0195165

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.

Highlights

Chlamydia trachomatis (Ct), a Gram-negative obligate intracellular bacterium, is the leading cause of bacterial sexually transmitted diseases worldwide with an estimated incidence of 105.7 million infections in adults every year [1]
The data from these experiments demonstrated that TLR3 had a biological impact on the innate immune response to Chlamydia infection in mice; the exact effect that TLR3 signaling had on the genital tract pathology of C. muridarum infection in mice was unclear
Our previous studies demonstrated that TLR3 signaling during C. muridarum infection plays a role in host defense and in the secretion of a variety of inflammatory mediators into the genital tracts of mice [25]

Summary

Introduction

Chlamydia trachomatis (Ct), a Gram-negative obligate intracellular bacterium, is the leading cause of bacterial sexually transmitted diseases worldwide with an estimated incidence of 105.7 million infections in adults every year [1]. Chlamydia trachomatis infections in the reproductive tract of women can lead to cervicitis and endometritis as well as to the development of serious complications, including pelvic inflammatory disease (PID), tubal scarring and infertility, fallopian tube blockage with serous fluid (hydrosalpinx), chronic pelvic pain, and ectopic pregnancy [2, 3]. Chlamydia infection causes the induction of a specific subset of innate inflammatory mediators and the recruitment of CD8+ T-cells into the female genital tract, and these factors are known to have a significant role in development of genital tract pathology [6,7,8]. The ultimate goal of the continued research on Ct pathogenesis is to identify immune mediators that generate long-term protective immune responses against Ct infections, and to ascertain immune targets that modulate the immune responses leading to upper reproductive tract pathology

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