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ABSTRACTChlamydiahas 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 muridarumspreads from the genital tract to the gastrointestinal tract potentially via the circulatory system. To test whether hematogenous C. muridarumcan spread to and establish a long-lasting colonization in the mouse gastrointestinal tract, we inoculated mice intravenously with a luciferase-expressing C. muridarumstrain 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 vivoimaging 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. muridarumorganisms at a lower dose in a different mouse strain also led to colonization of the gastrointestinal tract. We have demonstrated that intravenous C. muridaruminoculation 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.

The genital pathogen Chlamydiais known to colonize the gastrointestinal tract. Orally delivered Chlamydia muridarumcan reach the colon and maintain a long-lasting colonization there. However, C. muridarumwith mutations in chromosomal genes tc0237and tc0668(designated a chromosomal mutant) or deficient in plasmid-encoded pGP3 (designated a plasmid mutant) is unable to do so.

Although Chlamydia trachomatisis a human genital tract pathogen, chlamydial organisms have frequently been detected in both vaginal and rectal swab samples of animals and humans. The plasmid-encoded pGP3, a genital tract virulence factor, is essential for Chlamydia muridarumto colonize the mouse gastrointestinal tract.

ABSTRACTChlamydiahas been detected in the gastrointestinal tracts of humans and animals. We now report that gastrointestinal Chlamydia muridarumis able to induce robust transmucosal protection in mice. C. muridarumcolonization in the gastrointestinal tract correlated with both a shortened course of C. muridarumgenital tract infection and stronger protection against subsequent genital tract challenge infection. Mice preinoculated intragastrically with C. muridarumbecame highly resistant to subsequent C. muridaruminfection in the genital tract, resulting in prevention of pathology in the upper genital tract. The transmucosal protection in the genital tract was rapidly induced, durable, and dependent on major histocompatibility complex (MHC) class II antigen presentation but not MHC class I antigen presentation. Although a deficiency in CD4+T cells only partially reduced the transmucosal protection, depletion of CD4+T cells from B cell-deficient mice completely abolished the protection, suggesting a synergistic role of both CD4+T and B cells in the gastrointestinal C. muridarum-induced transmucosal immunity. However, the same protective immunity did not significantly affect C. muridarumcolonization in the gastrointestinal tract. The long-lasting colonization with C. muridarumwas restricted to the gastrointestinal tract and was nonpathogenic to either gastrointestinal or extragastrointestinal tissues. Furthermore, gastrointestinal C. muridarumdid not alter the gut microbiota or the development of gut mucosal resident memory T cell responses to a nonchlamydial infection. Thus, Chlamydiamay be developed into a safe and orally deliverable replicating vaccine for inducing transmucosal protection.

ABSTRACTThe cryptic plasmid is essential for Chlamydia muridarumdissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, a C. muridarumstrain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical for C. muridarumcolonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly, C. muridarumcolonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficient C. muridarumstrains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinal Chlamydia.

ABSTRACTChlamydiae colonize the gastrointestinal tracts of both animals and humans. However, their medical significance remains unknown. We have previously shown that wild-type Chlamydia muridarumspreads to and establishes stable colonization of the gastrointestinal tract following intravaginal inoculation. In the present study, we found that C. muridarumwith mutations in chromosomal genes tc0237and/or tc0668was defective in spreading to the mouse gastrointestinal tract, which correlated with its attenuated pathogenicity in the upper genital tract. This correlation was more consistent than that of chlamydial pathogenicity with ascending infection in the genital tract, since attenuated C. muridarumspread significantly less to the gastrointestinal tract but maintained robust ascending infection of the upper genital tract. Transcervical inoculation further confirmed the correlation between C. muridarumspreading to the gastrointestinal tract and its pathogenicity in the upper genital tract. Finally, defective spreading of C. muridarummutants was due to their inability to colonize the gastrointestinal tract since intragastric inoculation did not rescue the mutants' colonization. Thus, promoting C. muridarumcolonization of the gastrointestinal tract may represent a primary function of the TC0237 and TC0668 proteins. Correlation of chlamydial colonization of the gastrointestinal tract with chlamydial pathogenicity in the upper genital tract suggests a potential role for gastrointestinal chlamydiae in genital tract pathogenicity.