Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors

Morrison, Sandra G.; Giebel, Amanda M.; Toh, Evelyn; Spencer, Horace J.; Nelson, David E.; Morrison, Richard P.

doi:10.1128/iai.00141-18

Cited by 15 publications

(20 citation statements)

References 49 publications

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“…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.…”

Section: Fig 10supporting

confidence: 90%

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

Zhang

Huo

et al. 2019

Infect Immun

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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.

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Section: Fig 10supporting

confidence: 90%

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

Zhang

Huo

et al. 2019

Infect Immun

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“…It is worth noting that besides clone G28.51.1 (86,87), there are other C. muridarum mutants that have been shown to be defective in colonizing the GI tract and susceptible to IFN-␥ inhibition (88,89). A common property of these mutants is that they all carry mutations in chromosomal genes.…”

Section: Discussionmentioning

confidence: 99%

Evasion of Innate Lymphoid Cell-Regulated Gamma Interferon Responses by Chlamydia muridarum To Achieve Long-Lasting Colonization in Mouse Colon

et al. 2020

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Revealing the mechanisms by which bacteria establish long-lasting colonization in the gastrointestinal tract is an area of intensive investigation. The obligate intracellular bacterium Chlamydia is known to colonize mouse colon for long periods. A colonization-deficient mutant strain of this intracellular bacterium is able to regain long-lasting colonization in gamma interferon (IFN-γ) knockout mice following intracolon inoculation. We now report that mice deficient in conventional T lymphocytes or recombination-activating gene (Rag) failed to show rescue of mutant colonization. Nevertheless, antibody depletion of IFN-γ or genetic deletion of interleukin 2 (IL-2) receptor common gamma chain in Rag-deficient mice did rescue mutant colonization. These observations suggest that colonic IFN-γ, responsible for inhibiting the intracellular bacterial mutant, is produced by innate lymphoid cells (ILCs). Consistently, depletion of NK1.1+ cells in Rag-deficient mice both prevented IFN-γ production and rescued mutant colonization. Furthermore, mice deficient in transcriptional factor RORγt, but not chemokine receptor CCR6, showed full rescue of the long-lasting colonization of the mutant, indicating a role for group 3-like ILCs. However, the inhibitory function of the responsible group 3-like ILCs was not dependent on the natural killer cell receptor (NCR1), since NCR1-deficient mice still inhibited mutant colonization. Consistently, mice deficient in the transcriptional factor T-bet only delayed the clearance of the bacterial mutant without fully rescuing the long-lasting colonization of the mutant. Thus, we have demonstrated that the obligate intracellular bacterium Chlamydia maintains its long-lasting colonization in the colon by evading IFN-γ from group 3-like ILCs.

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“…First, it is unknown if Ct, like Cm, disseminates from the genital tract to the GI tract via an internal route (31), and Cm GI infections do not autoinoculate the genital tract in female mice (34). Second, only limited evidence supports the hypothesis that oral inoculation causes Ct GI infections in humans (4,41), whereas this is well established in the Cm mouse model (13,28). Finally, it is unknown if Ct GI infections induce transmucosal genital tract protective immune responses in humans.…”

Section: Discussionmentioning

confidence: 99%

“…GIAM-1 infects the lower GI tract and induces transmucosal protective immunity to WT Cm genital challenge. GI infections established either by the direct inoculation of Cm into the GI tract or by the dissemination of Cm from the genital tract to the GI tract are characterized by the continuous shedding of infectious chlamydiae from the GI tract in the absence of GI pathology (28,31,32). Because vaginal inoculation of GIAM-1 elicited a robust antibody response in the absence of a severely attenuated genital tract infection, we tested if GIAM-1 could infect the GI tract.…”

Section: Giam-1 Is Significantly Attenuated In a Murine Genital Tractmentioning

confidence: 99%

A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge

Morrison

Giebel

Toh

et al. 2020

mBio

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Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum. Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease. IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.

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Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors

Cited by 15 publications

References 49 publications

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

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

Evasion of Innate Lymphoid Cell-Regulated Gamma Interferon Responses by Chlamydia muridarum To Achieve Long-Lasting Colonization in Mouse Colon

A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge

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