Chlamydia muridarum Induces Pathology in the Female Upper Genital Tract via Distinct Mechanisms

Abstract

Sexually transmitted infection with Chlamydia trachomatis may lead to fibrotic blockage in women's upper genital tracts, resulting in tubal infertility. Intravaginal inoculation with C. muridarum readily induces fibrotic blockage or hydrosalpinx in mice and is used for investigating C. trachomatis pathogenicity. Using this model in combination with an antibody depletion approach, we confirmed CD4 ϩ T cell-mediated protective immunity and a CD8 ϩ T cell-dependent pathogenic mechanism during chlamydial infection in C57BL/6J mice. However, when mice genetically deficient in CD8 ϩ T cells were evaluated, we found, surprisingly, that these mice were still able to develop robust hydrosalpinx following C. muridarum infection, both contradicting the observation made in C57BL/6J mice and suggesting a pathogenic mechanism that is independent of CD8 ϩ T cells. We further found that depletion of CD4 ϩ T cells from CD8 ϩ T cell-deficient mice significantly reduced chlamydial induction of hydrosalpinx, indicating that CD4 ϩ T cells became pathogenic in mice genetically deficient in CD8 ϩ T cells. Since depletion of CD4 ϩ T cells both promoted chlamydial infection and reduced chlamydial pathogenicity in CD8 ϩ T cell-deficient mice, we propose that in the absence of CD8 ϩ T cells, some CD4 ϩ T cells may remain protective (as in C57BL/6J mice), while others may directly contribute to chlamydial pathogenicity. Thus, chlamydial pathogenicity can be mediated by distinct host mechanisms, depending upon host genetics and infection conditions. The CD8 ϩ T cell-deficient mouse model may be useful for further investigating the mechanisms by which CD4 ϩ T cells promote chlamydial pathogenicity.

Early Colonization of the Upper Genital Tract by Chlamydia muridarum Is Associated with Enhanced Inflammation Later in Infection

“…While CD4 ϩ T cells are necessary for Chlamydia clearance (5,22), antigen-nonspecific bystander CD4 ϩ T cells have been found to contribute to immunopathology in mice infected with C. trachomatis serovar D (23). Furthermore, it has been recently demonstrated that CD4 ϩ T cells can induce pathology in mice deficient in CD8 ϩ T cells, following C. muridarum infection (24). It is possible that the influx of CD4 ϩ T cells to the upper genital tract in mice following transcervical infection contributes not only to IFN-␥ production but also to immunopathology.…”

Chlamydia muridarum Alleviates Colitis via the IL-22/Occludin Signal Pathway

“…To quantitate live chlamydia, each swab was soaked in 0.5 ml of SPG buffer and vortexed with glass beads, and the chlamydial organisms released into the supernatants were titrated on HeLa cells. The infected cultures were processed for immunofluorescence assay as described previously [ 15 ]. A rabbit antibody (designated R1604, raised against purified C. muridarum EBs) was used as a primary antibody to label C. muridarum in HeLa cells and was then visualized with goat anti-rabbit IgG conjugated with Cy2 (green; Solarbio, SE131).…”

Suppression of Chlamydial Pathogenicity by Nonspecific CD8+T Lymphocytes

“…1. We have previously demonstrated that CD4 ϩ T cells are able to mediate chlamydial pathogenicity in CD8 KO mice (24). Interestingly, following adoptive transfer with CD8 ϩ T cells from OT1 mice, the recipient CD8 KO mice were no longer able to develop significant hydrosalpinx.…”

“…It is now recognized that clearance of chlamydial colonization from both genital (8) and small intestinal (23) mucosal tissues is dependent on Chlamydia-specific CD4 ϩ Th1 immunity. Besides a dominant role in protective immunity, CD4 ϩ T cells may also contribute to chlamydial pathogenicity under certain conditions, for example, in CD8 knockout (KO) mice (24). However, in most cases, CD8 ϩ T cells play a more dominant role in chlamydial pathogenesis since antibody depletion of CD8 ϩ T cells from wild-type C57BL/6J mice significantly reduced pathology induced by C. muridarum (21).…”

“…When wild-type CD8 ϩ T cells were adoptively transferred to OT1 mice, these mice regained the ability to develop hydrosalpinx in response to C. muridarum infection (26), confirming that the ability to detect chlamydial antigens is necessary for CD8 ϩ T cells to promote chlamydial pathogenicity. Despite the dominant role of Chlamydia-specific CD8 ϩ T cells in chlamydial pathogenesis, as demonstrated in both antibody depletion of CD8 ϩ T cells from C57BL/6J and transgenic OT1 mouse experimental settings, mice with genetic deficiency in CD8 or CD8 KO mice can still develop robust hydrosalpinx (24) because CD4 ϩ T cells can become pathogenic in these mice. Thus, depending on the infection conditions, either subset of Chlamydia-specific T cells may contribute chlamydial pathogenesis.…”