Demonstration of Persistent Infections and Genome Stability by Whole-Genome Sequencing of Repeat-Positive, Same-Serovar Chlamydia trachomatis Collected From the Female Genital Tract

Suchland, Robert J.; Dimond, Zoe; Putman, Tim; Rockey, Daniel D.

doi:10.1093/infdis/jix155

Cited by 26 publications

(23 citation statements)

References 34 publications

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“…The C. trachomatis plasmid is essential for establishing persistent infection in the female mouse GT. Ct infection causes persistent genital tract (GT) infection in humans that can persist for years (6)(7)(8)31). The Ct virulence factors required for the establishment of persistent infection are unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Ct infection causes persistent genital tract (GT) infection in humans that can persist for years ( 6 – 8 , 31 ). The Ct virulence factors required for the establishment of persistent infection are unknown.…”

Section: Resultsmentioning

confidence: 99%

“…A sequela of female infection is pelvic inflammatory disease (PID)-associated pathology that may result in tubal factor infertility and ectopic pregnancy (4). The pathophysiology of PID is not fully understood, but reinfection or persistent infection that drives damaging inflammatory immunopathology is thought to be important (5)(6)(7)(8)(9), which is corroborated by animal models of reinfection (10,11); conversely, animal models of persistent Ct infection that drive damaging pathology have not been reported.…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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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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“…The non-LGV parental strain was most likely a D/Da strain with E/F-like genomic backbone, i.e., belonging to clade T1 of the species tree (which involves prevalent genotypes) (Figure 2B and Supplemental Figure S1C). In fact, although NCBI BLAST analyses of the imported fragment found no single genome with 100% similarity, the “top” hits (query cover = 100%; percent identity > 99.75%) are serovar D/Da strains reported to belong to clade T1: D/13-96 (Putman et al 2013; Hadfield et al 2017), D/SotonD1 (Harris et al 2012), D/SQ29 and D/SQ32 (Suchland et al 2017). The T1 donor backbone is also strongly supported by the existence of multiple SNVs within the transferred region perfectly segregating T1 strains and also SNVs that are exclusive of serovar D/Da strains with E/F-like genome profile (Figure 2B and Supplemental Figure S1C).…”

Section: Resultsmentioning

confidence: 99%

Chlamydia trachomatisoutbreak: when the virulence-associated genome backbone imports a prevalence-associated major antigen signature

Borges

Cordeiro

Salas

et al. 2019

Preprint

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Chlamydia trachomatisis the most prevalent sexually transmitted bacteria worldwide and the causative agent of blinding trachoma. Strains are classified based onompAgenotypes, which are strongly linked with differential tissue tropism and disease outcomes. A lymphogranuloma venereum (LGV) epidemics, characterized by ulcerative proctitis, has emerged in the last two decades (mainly L2b genotype), raising high concern especially due to its circulation among men who have sex with men (MSM). Here, we report an ongoing outbreak (mostly affecting HIV-positive MSM engaging in high-risk practices) caused by an L2b strain with a rather unique genome makeup that precluded the laboratory notification of this outbreak as LGV due to its non-LGVompAsignature. Homologous recombination mediated the transfer of a ~4.5Kbp fragment enrollingCT681/ompAand neighboring genes (CT677/rrf, CT678/pyrH, CT679/tsf, CT680/rpsB) from a serovar D/Da strain likely possessing the typical T1 clade genome backbone associated with most prevalent genotypes (E and F). The hybrid L2b/D-Da strain presents the adhesin and immunodominant antigen MOMP (coded byompA) with an epitope repertoire typical of non-invasive genital strains, while keeping the genome-dispersed virulence fingerprint of a classical LGV (L2b) strain. As previously reported for inter-cladeompAexchange among non-LGV clades, this unprecedentedC. trachomatisgenomic mosaic involving a contemporary epidemiologically and clinically relevant LGV strain may have implications on its transmission, tissue tropism and pathogenic capabilities. The emergence of such variants with epidemic and pathogenic potential highlights the need of more oriented surveillance strategies focused on capturing the C.trachomatisevolution in action.

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“…Altering between infectious elementary body (EB) and the dividing reticulate body (RB), this obligate intracellular pathogen multiplies within the membrane-bound vacuoles termed inclusions (3). Under stress conditions, C. trachomatis can enter into a viable noninfectious persistent growth state, which has been linked to chronic Chlamydia infections (2,(4)(5)(6). Antimicrobials that eradicate all chlamydial life forms may especially be of benefit clinically (7).…”

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confidence: 99%

Potency of Solithromycin against Fast- and Slow-Growing Chlamydial Organisms

Gao

Wang

Zeng

et al. 2018

Antimicrob Agents Chemother

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Evidence is provided that solithromycin is a bactericidal against not only fast-growing chlamydial organisms but also those slowed by gamma interferon (IFN-γ) At sublethal concentrations, Sol impedes homotypic fusion of-containing vacuoles and reduces secretion of the type III secretion (T3S) effector IncA. Sol may therefore represent a potential new clinical treatment for infections. Selective perturbation of the T3S system suggests a novel mode of antibacterial action for Sol that warrants further investigation.

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Demonstration of Persistent Infections and Genome Stability by Whole-Genome Sequencing of Repeat-Positive, Same-Serovar Chlamydia trachomatis Collected From the Female Genital Tract

Abstract: These data demonstrate examples of long-term persistence in patients in the face of repeated antibiotic therapy and show that pathogen mutational strategies are not important in persistence of this pathogen in patients.

Cited by 26 publications

References 34 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

Chlamydia trachomatisoutbreak: when the virulence-associated genome backbone imports a prevalence-associated major antigen signature

Potency of Solithromycin against Fast- and Slow-Growing Chlamydial Organisms

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