Caspase-1 Contributes toChlamydia trachomatis-Induced Upper Urogenital Tract Inflammatory Pathologies without Affecting the Course of Infection

Abstract

Chlamydia trachomatis infection induces inflammatory pathologies in the upper genital tract, potentially leading to ectopic pregnancy and infertility in the affected women. Caspase-1 is required for processing and release of the inflammatory cytokines interleukin-1␤ (IL-1␤), IL-18, and possibly IL-33. In the present study, we evaluated the role of caspase-1 in chlamydial infection and pathogenesis. Although chlamydial infection induced caspase-1 activation and processing of IL-1␤, mice competent and mice deficient in caspase-1 experienced similar courses of chlamydial infection in their urogenital tracts, suggesting that Chlamydia-activated caspase-1 did not play a significant role in resolution of chlamydial infection. However, when genital tract tissue pathologies were examined, the caspase-1-deficient mice displayed much reduced inflammatory damage. The reduction in inflammation was most obvious in the fallopian tube tissue. These observations demonstrated that although caspase-1 is not required for controlling chlamydial infection, caspase-1-mediated responses can exacerbate the Chlamydia-induced inflammatory pathologies in the upper genital tract, suggesting that the host caspase-1 may be targeted for selectively attenuating chlamydial pathogenicity without affecting the host defense against chlamydial infection.

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

“…5), because this is a most commonly used method for monitoring chlamydial infection in mice (35,40,49). MyD88 KO mice only displayed a slightly increased shedding intensity and duration, which is consistent with a previous observation (35) but still surprising to us given the severe deficiency in early inflammation and the strongly Th2-biased adaptive response in the MyD88 KO mice.…”

“…The organisms were propagated, purified, aliquoted, and stored as described previously (39,40). Female C57BL/6J mice wild type (stock number 000664; The Jackson Laboratory, Bar Harbor, ME) or with gene deficiency in MyD88 (a gift from Dr. S. Akira, Osaka University, Osaka, Japan) were used at the age of 7-8 wk old.…”

“…The infected cultures were incubated for 24 h at 37˚C in a CO 2 incubator before harvesting for cytokine measurement by ELISA. To infect HeLa cells, HeLa cells grown on coverslips in 24-well plates containing DMEM (Life Technologies, Rockville, MD) with 10% FCS (Life Technologies) at 37˚C in an incubator supplied with 5% CO 2 were inoculated with C. muridarum organisms as described previously (39,40). The infected cultures were processed for immunofluorescence assay as described below.…”

Distinct Roles of CD28- and CD40 Ligand-Mediated Costimulation in the Development of Protective Immunity and Pathology duringChlamydia muridarumUrogenital Infection in Mice

“…CCL2). The organisms were propagated, purified, divided into aliquots, and stored as described previously (7,8 …”

Intravenous Inoculation with Chlamydia muridarum Leads to a Long-Lasting Infection Restricted to the Gastrointestinal Tract

“…This is because a single inoculation of C. muridarum organisms in the mouse lower genital tract can cause hydrosalpinx and infertility (7)(8)(9), closely mimicking the tubal adhesion, hydrosalpinx, and infertility observed in women urogenitally infected with C. trachomatis (10)(11)(12). Although C. muridarum is not a natural sexually transmitted agent of mice, chlamydiologists have used this model not only to identify both chlamydial (13)(14)(15)(16)(17) and host (1,5,(18)(19)(20)(21)(22)(23)(24) pathogenic determinants but also to define the roles of ascending infection and tubal inflammation in chlamydial induction of hydrosalpinx (9,16,25,26). Nevertheless, questions such as how a self-limited infection with C. muridarum in the mouse genital tract can trigger tubal fibrosis or hydrosalpinx that lasts long after the tubal infection is resolved (9,25) remain unanswered.…”