<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

ABSTRACT 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 prope...

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Autores principales:	Chunfu Yang, Laszlo Kari, Lei Lei, John H. Carlson, Li Ma, Claire E. Couch, William M. Whitmire, Kevin Bock, Ian Moore, Christine Bonner, Grant McClarty, Harlan D. Caldwell
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Chlamydia plasmid persistent infection antimicrobial peptides Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a68574616a9f47c08102b25a02377363
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spelling	oai:doaj.org-article:a68574616a9f47c08102b25a023773632021-11-15T15:56:44Z<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology10.1128/mBio.01902-202150-7511https://doaj.org/article/a68574616a9f47c08102b25a023773632020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01902-20https://doaj.org/toc/2150-7511ABSTRACT 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.Chunfu YangLaszlo KariLei LeiJohn H. CarlsonLi MaClaire E. CouchWilliam M. WhitmireKevin BockIan MooreChristine BonnerGrant McClartyHarlan D. CaldwellAmerican Society for MicrobiologyarticleChlamydiaplasmidpersistent infectionantimicrobial peptidesMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chlamydia plasmid persistent infection antimicrobial peptides Microbiology QR1-502
spellingShingle	Chlamydia plasmid persistent infection antimicrobial peptides Microbiology QR1-502 Chunfu Yang Laszlo Kari Lei Lei John H. Carlson Li Ma Claire E. Couch William M. Whitmire Kevin Bock Ian Moore Christine Bonner Grant McClarty Harlan D. Caldwell <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
description	ABSTRACT 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.
format	article
author	Chunfu Yang Laszlo Kari Lei Lei John H. Carlson Li Ma Claire E. Couch William M. Whitmire Kevin Bock Ian Moore Christine Bonner Grant McClarty Harlan D. Caldwell
author_facet	Chunfu Yang Laszlo Kari Lei Lei John H. Carlson Li Ma Claire E. Couch William M. Whitmire Kevin Bock Ian Moore Christine Bonner Grant McClarty Harlan D. Caldwell
author_sort	Chunfu Yang
title	<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
title_short	<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
title_full	<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
title_fullStr	<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
title_full_unstemmed	<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology
title_sort	<named-content content-type="genus-species">chlamydia trachomatis</named-content> plasmid gene protein 3 is essential for the establishment of persistent infection and associated immunopathology
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/a68574616a9f47c08102b25a02377363
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<named-content content-type="genus-species">Chlamydia trachomatis</named-content> Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

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