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

Abstract

cChlamydia has been detected in the gastrointestinal tracts of both animals and humans. However, it remains unclear whether the chlamydial organisms can be introduced into the gastrointestinal tract via pathways independent of the oral and anal routes. We have recently shown that Chlamydia muridarum spreads from the genital tract to the gastrointestinal tract potentially via the circulatory system. To test whether hematogenous C. muridarum can spread to and establish a long-lasting colonization in the mouse gastrointestinal tract, we inoculated mice intravenously with a luciferase-expressing C. muridarum strain and monitored its distribution. After tail vein inoculation, most luciferase-generated bioluminescence signals were detected in the mouse abdominal area throughout the experiment. The ex vivo imaging revealed that the abdominal signals came from the gastrointestinal tract tissues. Simultaneous monitoring of chlamydial organisms in individual organs or tissues revealed an initial stage of systemic spreading followed by a long-lasting infection in the gastrointestinal tract. A retro-orbital vein inoculation of the C. muridarum organisms at a lower dose in a different mouse strain also led to colonization of the gastrointestinal tract. We have demonstrated that intravenous C. muridarum inoculation can result in colonization of the gastrointestinal tract, suggesting that the chlamydial organisms may use the sexual behavior-independent circulation pathway to infect the gastrointestinal tract.C hlamydia muridarum infection in the mouse genital tract model has been used for investigation of the mechanisms of Chlamydia trachomatis pathogenesis and immune responses (1-6). This is because a single inoculation of C. muridarum organisms in the mouse lower genital tract can cause hydrosalpinx and infertility (7-9), closely mimicking the tubal adhesion, hydrosalpinx, and infertility observed in women urogenitally infected with C. trachomatis (10-12). Although C. muridarum is not a natural sexually transmitted agent of mice, chlamydiologists have used this model not only to identify both chlamydial (13-17) and host (1, 5, 18-24) 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.Although C. trachomatis is a sexually transmitted bacterial pathogen that causes pathologies in the genital tract (27, 28), it has also been detected in the gastrointestinal (GI) tract of humans (29-32). C. muridarum colonized the mouse GI tract when it was introduced to multiple mucosae (33) and established a long-lasting infection when directly inoculated into the mouse GI tract (34,35). The question is whether persistent colonization of the mouse GI tract can fill in the temporal gap between the self-limited infection...

Antigen-Specific CD4+T Cell-Derived Gamma Interferon Is Both Necessary and Sufficient for ClearingChlamydiafrom the Small Intestine but Not the Large Intestine

“…For intragastric inoculation, EBs diluted in 100 l of SPG that contained 2 ϫ 10 5 IFU or the desired number of IFU as indicated for individual experiments were delivered to the stomach using a straight-balled end needle designed for mouse oral gavage (N-PK 020; Braintree Scientific Inc., Braintree, MA). Following the initial inoculation, both vaginal and rectal swabs were taken periodically or organs/tissues were harvested (after mice were sacrificed) for titration of viable organisms as described previously (20,21,26). In some experiments, mice were treated with an anti-CD4 antibody, while in others, exogenous molecules or donor T cells were provided as described below.…”

Chlamydia muridarum with Mutations in Chromosomal Genes tc0237 and/or tc0668 Is Deficient in Colonizing the Mouse Gastrointestinal Tract

“…Although chlamydial organisms have been detected in the GI tracts of both human and animal hosts (26-28, 30, 31, 33-44) and C. muridarum is known to colonize the GI tract for long periods of time (26,(30)(31)(32)(33), the medical significance of these phenomena remains unclear. Here, we present the first experimental evidence of a correlation of C. muridarum spreading to and colonization of the GI tract with its pathogenicity in the upper genital tract.…”

“…The organs and tissue segments were homogenized in cold SPG buffer. Live C. muridarum organisms released into swab suspensions or tissue supernatants were titrated on HeLa cells in duplicate as described previously (6,19,20,26,31,32). The total number of IFUs per swab or tissue sample was converted into log 10 for calculation of the mean and standard deviation across mice in the same group at each time point.…”

“…Spreading was independent of the oral-fecal route since singly housed mice restrained from taking up mouse secretions still showed C. muridarum spreading from the genital to the GI tract (26,28). A hematogenous route might mediate the spreading because C. muridarum survived in the blood and hematogenous C. muridarum established long-lasting colonization restricted to the GI tract (31). In addition, C. muridarum failed to autoinoculate the genital tract after colonization of the GI tract of the same mouse for 70 days (32), suggesting that GI tract C. muridarum may have to use an indirect mechanism to impact chlamydial pathogenicity in the genital tract.…”

Chlamydia trachomatis Genital Infections

“…Recent studies have revealed that long lasting C. muridarum colonization of the murine gastrointestinal (GI) tract can be established with very low inocula administered orally 137. Intravenous inoculation with a bioluminescent derivative of C. muridarum also resulted in GI colonization 138, revealing a systemic route to this mucosal site. Treatment with doxycycline cleared GI infection but azithromycin treatment was ineffective 139.…”