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

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Although Chlamydia trachomatis is 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 muridarum to colonize the mouse gastrointestinal tract. However, intracolon inoculation to bypass the gastric barrier rescued the colonization ability of a pGP3-deficient C. muridarum mutant, suggesting that pGP3 is required for C. muridarum to reach but not to colonize the large intestine. The pGP3-deficient mutant was rapidly cleared in the stomach and was 100-fold more susceptible to gastric killing. In mice genetically deficient in gastrin, a key regulator for gastric acid production, or pharmacologically treated with a proton pump inhibitor, the ability of pGP3-deficient C. muridarum to colonize the gastrointestinal tract was rescued. The pGP3-dependent resistance was further recapitulated in vitro with treatments with HCl, pepsin, or sarkosyl. In the genital tract, deficiency in pGP3 significantly reduced C. muridarum survival in the mouse vagina and increased C. muridarum susceptibility to vaginal killing by ϳ8 times. The pGP3-deficient C. muridarum was more susceptible to lactic acid killing, and the pGP3 deficiency also significantly increased C. trachomatis susceptibility to lactic acid. The above-described observations together suggest that Chlamydia may have acquired the plasmidencoded pGP3 to overcome the gastric barrier during its adaptation to the gastrointestinal tract and the pGP3-dependent resistance may enable chlamydial evasion of the female lower genital tract barrier during sexual transmission.

Section: Fig 10supporting

confidence: 90%

mentioning

confidence: 93%

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

Zhang

Huo

et al. 2019

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…C. muridarum EBs were used to inoculate 6-to 7-week-old female mice (Jackson Laboratories, Inc., Bar Harbor, ME) intravaginally or intragastrically as described previously (10,20,26,48). The following mice were used in the current study.…”

Section: Methodsmentioning

confidence: 99%

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

Lin

Koprivsek

et al. 2019

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The genital tract pathogen Chlamydia trachomatis is frequently detected in the gastrointestinal tract, but the host immunity that regulates chlamydial colonization in the gut remains unclear. In a Chlamydia muridarum-C57 mouse model, chlamydial organisms are cleared from the genital tract in ϳ4 weeks, but the genital organisms can spread to the gastrointestinal tract. We found that the gastrointestinal chlamydial organisms were cleared from the small intestine by day 28, paralleling their infection course in the genital tract, but persisted in the large intestine for long periods. Mice deficient in ␣/␤ T cells or CD4 ϩ T cells but not CD8 ϩ T cells showed chlamydial persistence in the small intestine, indicating a critical role for CD4 ϩ T cells in clearing Chlamydia from the small intestine. The CD4 ϩ T cell-dependent clearance is likely mediated by gamma interferon (IFN-␥), since mice deficient in IFN-␥ but not interleukin 22 (IL-22) signaling pathways rescued chlamydial colonization in the small intestine. Furthermore, exogenous IFN-␥ was sufficient for clearing Chlamydia from the small intestine but not the large intestine. Mice deficient in developing Chlamydia-specific Th1 immunity showed chlamydial persistence in the small intestine. Finally, IFN-␥-producing CD4 ϩ but not CD8 ϩ T cells from immunized donor mice were sufficient for eliminating Chlamydia from the small intestine but not the large intestine of recipient mice. Thus, we have demonstrated a critical role for Th1 immunity in clearing Chlamydia from the small intestine but not the large intestine, indicating that chlamydial colonization in different regions of the gastrointestinal tract is regulated by distinct immune mechanisms.

“…C. muridarum EBs were used to inoculate 6-to 7-week-old female mice (The Jackson Laboratory, Inc., Bar Harbor, ME) intravaginally as described previously (10,49,51,52). The mouse strains used in the current study included wild-type C57BL/6J mice (stock number 0006640; The Jackson Laboratory) and mice deficient in CD8 ϩ T cells, designated B6.129S2-Cd8a tm1Mak /J mice (stock number 002665; The Jackson Laboratory).…”

Section: Methodsmentioning

confidence: 99%

Chlamydia muridarum Induces Pathology in the Female Upper Genital Tract via Distinct Mechanisms

Lin

Xie

et al. 2019

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Sexually transmitted infection with Chlamydia trachomatis may lead to fibrotic blockage in women's upper genital tracts, resulting in tubal infertility. Intravaginal inoculation with C. muridarum readily induces fibrotic blockage or hydrosalpinx in mice and is used for investigating C. trachomatis pathogenicity. Using this model in combination with an antibody depletion approach, we confirmed CD4 ϩ T cell-mediated protective immunity and a CD8 ϩ T cell-dependent pathogenic mechanism during chlamydial infection in C57BL/6J mice. However, when mice genetically deficient in CD8 ϩ T cells were evaluated, we found, surprisingly, that these mice were still able to develop robust hydrosalpinx following C. muridarum infection, both contradicting the observation made in C57BL/6J mice and suggesting a pathogenic mechanism that is independent of CD8 ϩ T cells. We further found that depletion of CD4 ϩ T cells from CD8 ϩ T cell-deficient mice significantly reduced chlamydial induction of hydrosalpinx, indicating that CD4 ϩ T cells became pathogenic in mice genetically deficient in CD8 ϩ T cells. Since depletion of CD4 ϩ T cells both promoted chlamydial infection and reduced chlamydial pathogenicity in CD8 ϩ T cell-deficient mice, we propose that in the absence of CD8 ϩ T cells, some CD4 ϩ T cells may remain protective (as in C57BL/6J mice), while others may directly contribute to chlamydial pathogenicity. Thus, chlamydial pathogenicity can be mediated by distinct host mechanisms, depending upon host genetics and infection conditions. The CD8 ϩ T cell-deficient mouse model may be useful for further investigating the mechanisms by which CD4 ϩ T cells promote chlamydial pathogenicity.