Despite the extensive efforts, there is still a lack of a licensed vaccine against
Chlamydia trachomatis
in humans. The mouse genital tract infection with
Chlamydia muridarum
has been used to both investigate chlamydial pathogenic mechanisms and evaluate vaccine candidates due to the
C. muridarum’s
ability to induce mouse hydrosalpinx.
C. muridarum
mutants lacking the entire plasmid or deficient in only the plasmid-encoded pGP3 are highly attenuated in inducing hydrosalpinx. We now report that intravaginal immunization with these mutants as live attenuated vaccines protected mice from hydrosalpinx induced by wild type
C. muridarum
. However, these mutants still productively infected the mouse genital tract. Further, the mutant-infected mice were only partially protected against the subsequent infection with wild type
C. muridarum
. Thus, these mutants as vaccines are neither safe nor effective when they are delivered via the genital tract. Interestingly, these mutants were highly deficient in colonizing the gastrointestinal tract. Particularly, the pGP3-deficient mutant failed to shed live organisms from mice following an oral inoculation, suggesting that the pGP3-deficient mutant may be developed into a safe oral vaccine. Indeed, oral inoculation with the pGP3-deficient mutant induced robust transmucosal immunity against both the infection and pathogenicity of wild type
C. muridarum
in the genital tract. Thus, we have demonstrated that the plasmid-encoded virulence factor pGP3 may be targeted for developing an attenuated live oral vaccine.
Sexually transmitted Chlamydia, which can cause fibrotic pathology in women’s genital tracts, is also frequently detected in the gastrointestinal tract. However, the medical significance of the gastrointestinal Chlamydia remains unclear. A murine Chlamydia readily spreads from the mouse genital tract to the gastrointestinal tract while inducing oviduct fibrotic blockage or hydrosalpinx. We previously proposed a two-hit model in which the mouse gastrointestinal Chlamydia might induce the second hit to promote genital tract pathology, and we are now providing experimental evidence for testing the hypothesis. First, chlamydial mutants that are attenuated in inducing hydrosalpinx in the genital tract also reduce their colonization in the gastrointestinal tract, leading to a better correlation of chlamydial induction of hydrosalpinx with chlamydial colonization in the gastrointestinal tract than in the genital tract. Second, intragastric coinoculation with a wild-type Chlamydia rescued an attenuated Chlamydia mutant to induce hydrosalpinx, while the chlamydial mutant infection in the genital tract alone was unable to induce any significant hydrosalpinx. Finally, the coinoculated gastrointestinal Chlamydia failed to directly spread to the genital tract lumen, suggesting that gastrointestinal Chlamydia may promote genital pathology via an indirect mechanism. Thus, we have demonstrated a significant role of gastrointestinal Chlamydia in promoting pathology in the genital tract possibly via an indirect mechanism. This study provides a novel direction/dimension for further investigating chlamydial pathogenic mechanisms.
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