The cryptic plasmid is more important for Chlamydia muridarum to colonize the mouse gastrointestinal tract than to infect the genital tract

Abstract

Chlamydia has been detected in the gastrointestinal tracts of both animals and humans. However, the mechanism by which Chlamydia colonizes the gut remains unclear. Chlamydia muridarum is known to spread from the genital to the gastrointestinal tracts hematogenously. The C. muridarum plasmid is a key pathogenic determinant in the mouse upper genital tract although plasmid-deficient C. muridarum is still able to colonize the upper genital tract. We now report that plasmid-deficient C. muridarum exhibits significantly delayed/reduced spreading from the mouse genital to the gastrointestinal tracts. C. muridarum with or without plasmid maintained similar levels in the mouse circulatory system following intravenous inoculation but the hematogenous plasmid-deficient C. muridarum was significantly less efficient in colonizing the gastrointestinal tract. Consistently, plasmid-deficient C. muridarum failed to restore normal colonization in the gastrointestinal tract even after intragastric inoculation at a high dose. Thus, we have demonstrated a plasmid-dependent colonization of C. muridarum in the gastrointestinal tract, supporting the concept that C. muridarum may have acquired the plasmid for adaptation to the mouse gastrointestinal tract during oral-fecal transmission. Since the plasmid is more important for C. muridarum to colonize the gastrointestinal tract than to infect the genital tract, the current study has laid a foundation for further defining the host pathways targeted by the plasmid-encoded or -regulated chlamydial effectors.

The Plasmid-Encoded pGP3 Promotes Chlamydia Evasion of Acidic Barriers in Both Stomach and Vagina

“…It is worth noting that deficiency in pGP3 reduced C. muridarum survival in the stomach by more than 100-fold, while the reduction in survival in the vagina was only ϳ8-fold. This discrepancy is consistent with previous observations that loss-of-function mutations in genes carried in the C. muridarum plasmid or genome caused a more dramatic phenotype in the GI tract than in the genital tract (28)(29)(30)53). The GI tract antimicrobial machineries, such as gastric acid and digestive hydrolases, are more robust than those in the genital tract.…”

“…Recent studies have shown that vaginal C. muridarum can not only ascend to the oviduct but also spread to the GI tract (26) via a hematogenous route (27) to establish long-lasting colonization in the GI tract. Interestingly, this genital-to-GI-tract spreading seems to correlate with C. muridarum induction of hydrosalpinx in the genital tract (28)(29)(30). These observations have led to the proposal of a two-hit model partially explaining C. muridarum pathogenicity in the upper genital tract (7).…”

“…It is not clear how C. muridarum overcomes the gastric barrier and achieves long-lasting colonization in the colon. We have recently shown that both the cryptic plasmid and its encoded pGP3 are important for C. muridarum to colonize the GI tract (28,30). However, the precise mechanisms by which pGP3 promotes C. muridarum colonization in the GI tract remain unknown.…”

“…In the current study, we have used the C. muridarum mouse model to investigate mechanisms of C. muridarum colonization in the GI tract by focusing on pGP3 (28,30). Interestingly, by using an intracolon inoculation to bypass the gastric barrier, the ability of a pGP3-deficient C. muridarum mutant to colonize the GI tract for a long period of time was rescued, suggesting that pGP3 is required for C. muridarum to overcome barriers in the upper GI tract but not the colon.…”

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

“…C. trachomatis is naturally transmitted among humans sexually, while C. muridarum may be naturally transmitted among mice via the oral-fecal route (instead of sexually). This is because the C. muridarum plasmid or plasmid-encoded proteins or some chromosomal proteins have been shown to be more important for C. muridarum to colonize the GI tract than to infect the genital tract (47,48). In addition, the C. muridarum genome still maintains three copies of a full-length cytotoxin gene with significant homology to genes for large clostridial cytotoxins (49).…”