Rectal administration of a chlamydial subunit vaccine protects against genital infection and upper reproductive tract pathology in mice

Pais, Roshan; Omosun, Yusuf; He, Qing; Blás-Machado, Uriel; Black, Carolyn M.; Igietseme, Joseph U.; Fujihashi, Kohtaro; Eko, Francis O.

doi:10.1371/journal.pone.0178537

Cited by 21 publications

(27 citation statements)

References 51 publications

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“…1C and D ). These pathological findings are similar to those reported by other investigators using urogenital Ct strains in mice ( 34 , 35 ). In contrast, CtD P − -infected mice exhibited no, or only minimal, uterine horn dilation ( Fig.…”

Section: Resultssupporting

confidence: 92%

Chlamydia trachomatis Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

Yang

Kari

Lei

et al. 2020

mBio

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Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes blinding trachoma and sexually transmitted disease afflicting hundreds of millions of people globally. A fundamental but poorly understood pathophysiological characteristic of chlamydial infection is the propensity to cause persistent infection that drives damaging inflammatory disease. The chlamydial plasmid is a virulence factor, but its role in the pathogenesis of persistent infection capable of driving immunopathology is unknown. Here, we show by using mouse and nonhuman primate infection models that the secreted plasmid gene protein 3 (Pgp3) is essential for establishing persistent infection. Ppg3-dependent persistent genital tract infection resulted in a severe endometritis caused by an intense infiltration of endometrial submucosal macrophages. Pgp3 released from the cytosol of lysed infected oviduct epithelial cells, not organism outer membrane-associated Pgp3, inhibited the chlamydial killing activity of antimicrobial peptides. Genetic Pgp3 rescue experiments in cathelin-related antimicrobial peptide (CRAMP)-deficient mice showed Pgp3-targeted antimicrobial peptides to subvert innate immunity as a pathogenic strategy to establish persistent infection. These findings provide important advances in understanding the role of Pgp3 in the pathogenesis of persistent chlamydial infection and associated immunopathology. IMPORTANCE Chlamydia trachomatis can cause persistent infection that drives damaging inflammatory responses resulting in infertility and blindness. Little is known about chlamydial genes that cause persistence or factors that drive damaging pathology. In this work, we show that the C. trachomatis plasmid protein gene 3 (Pgp3) is the essential virulence factor for establishing persistent female genital tract infection and provide supportive evidence that Pgp3 functions similarly in a nonhuman primate trachoma model. We further show that persistent Ppg3-dependent infection drives damaging immunopathology. These results are important advances in understanding the pathophysiology of chlamydial persistence.

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Section: Resultssupporting

confidence: 92%

Chlamydia trachomatis Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

Yang

Kari

Lei

et al. 2020

mBio

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“…This type of pathology was also observed in other recent studies. 6,48,49 Pathology in the oviducts, more specifically hydrosalpinx, is a known pathological marker for infertility in mice. Others have, however, also observed a correlation between infertility and uterine horn and glandular duct dilation, 49 and the TC model (using C.t.)…”

Section: Discussionmentioning

confidence: 99%

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge

et al. 2020

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The optimal protective immunity against Chlamydia trachomatis (C.t.) is still not fully resolved. One of the unresolved issues concerns the importance of resident immunity, since a recent study showed that optimal protection against a transcervical (TC) infection required genital tissue-resident memory T cells. An important question in the Chlamydia field is therefore if a parenteral vaccine strategy, inducing only circulating immunity primed at a nonmucosal site, should be pursued by Chlamydia vaccine developers. To address this question we studied the protective efficacy of a parenteral Chlamydia vaccine, formulated in the Th1/ Th17 T cell-inducing adjuvant CAF01. We found that a parenteral vaccination induced significant protection against a TC infection and against development of chronic pathology. Protection correlated with rapid recruitment of Th1/Th17 T cells to the genital tract (GT), which efficiently prevented infection-driven generation of low quality Th1 or Th17 T cells, and instead maintained a pool of high quality multifunctional Th1/Th17 T cells in the GT throughout the infection. After clearance of the infection, a pool of these cells settled in the GT as tissue-resident Th1 and Th17 cells expressing CD69 but not CD103, CD49d, or CCR7, where they responded rapidly to a reinfection. These results show that a nonmucosal parenteral strategy inducing Th1 and Th17 T cells mediates protection against both infection with C.t. as well as development of chronic pathology, and lead to post-challenge protective tissue-resident memory immunity in the genital tract.npj Vaccines (2020) 5:7 ; https://doi.

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“…Although being a human pathogen, C . trachomatis has been widely used in murine infection studies to unravel antibacterial cell autonomous mechanisms and for studying novel vaccination strategies [ 38 ]. In this study, it is shown that not only mGBP1 and mGBP2 [ 30 , 33 ], but the majority of mGBPs colocalize with chlamydia inclusions.…”

Section: Discussionmentioning

confidence: 99%

Broad recruitment of mGBP family members to Chlamydia trachomatis inclusions

et al. 2017

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Chlamydia, the most common sexually transmitted pathogen, is an exquisitely adapted Gram-negative obligate intracellular bacterium. Intracellular Chlamydia trachomatis replicate in a specialized vacuole, termed inclusion, which shields the bacterium from antimicrobial immunity of the host cells and acts as a signalling interface. Previously it was shown that members of the interferon induced guanylate binding protein (mGBP) family, in particular murine GBP1 and mGBP2, were found to accumulate at the bacterial inclusions, similar to previously published recruitment of GBPs to the parasitophorous vacuole of Toxoplasma gondii. Here, we provide a wide comparison of mGBPs roles within the host cell in the context of Chlamydia and Toxoplasma infection. By confocal microscopy on fixed and living infected cells we show localization of mGBP3, mGBP6, mGBP7, mGBP9, and mGBP10, in addition to mGBP1 and mGBP2, at chlamydia inclusions. In time lapse videos using GFP expressing Chlamydia we show rapid and transient dynamics of mGBP9 accumulation onto chlamydia inclusions. Taken together this study reveals a broad activation of mGBP recruitment towards Chlamydia trachomatis inclusions after infection and provides evidence for time limited action of mGBP9 at the chlamydia inclusion.

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Rectal administration of a chlamydial subunit vaccine protects against genital infection and upper reproductive tract pathology in mice

Cited by 21 publications

References 51 publications

Chlamydia trachomatis Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

Chlamydia trachomatis Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge

Broad recruitment of mGBP family members to Chlamydia trachomatis inclusions

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