Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon

ABSTRACT Clinical persistence of Chlamydia trachomatis (Ct) sexually transmitted infections (STIs) is a major public health concern. In vitro persistence is known to develop through interferon gamma (IFN-γ) induction of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, an essential am...

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Autores principales:	Naraporn Somboonna, Noa Ziklo, Thomas E. Ferrin, Jung Hyuk Suh, Deborah Dean
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Chlamydia trachomatis indole interferon gamma sexually transmitted infections trpA tryptophan synthesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8e023c33226040bcb3d0601379d86a27
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spelling	oai:doaj.org-article:8e023c33226040bcb3d0601379d86a272021-11-15T16:22:10ZClinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon10.1128/mBio.01464-192150-7511https://doaj.org/article/8e023c33226040bcb3d0601379d86a272019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01464-19https://doaj.org/toc/2150-7511ABSTRACT Clinical persistence of Chlamydia trachomatis (Ct) sexually transmitted infections (STIs) is a major public health concern. In vitro persistence is known to develop through interferon gamma (IFN-γ) induction of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, an essential amino acid for Ct replication. The organism can recover from persistence by synthesizing tryptophan from indole, a substrate for the enzyme tryptophan synthase. The majority of Ct strains, except for reference strain B/TW-5/OT, contain an operon comprised of α and β subunits that encode TrpA and TrpB, respectively, and form a functional αββα tetramer. However, trpA mutations in ocular Ct strains, which are responsible for the blinding eye disease known as trachoma, abrogate tryptophan synthesis from indole. We examined serial urogenital samples from a woman who had recurrent Ct infections over 4 years despite antibiotic treatment. The Ct isolates from each infection episode were genome sequenced and analyzed for phenotypic, structural, and functional characteristics. All isolates contained identical mutations in trpA and developed aberrant bodies within intracellular inclusions, visualized by transmission electron microscopy, even when supplemented with indole following IFN-γ treatment. Each isolate displayed an altered αββα structure, could not synthesize tryptophan from indole, and had significantly lower trpBA expression but higher intracellular tryptophan levels compared with those of reference Ct strain F/IC-Cal3. Our data indicate that emergent mutations in the tryptophan operon, which were previously thought to be restricted only to ocular Ct strains, likely resulted in in vivo persistence in the described patient and represents a novel host-pathogen adaptive strategy for survival. IMPORTANCE Chlamydia trachomatis (Ct) is the most common sexually transmitted bacterium with more than 131 million cases occurring annually worldwide. Ct infections are often asymptomatic, persisting for many years despite treatment. In vitro recovery from persistence occurs when indole is utilized by the organism’s tryptophan synthase to synthesize tryptophan, an essential amino acid for replication. Ocular but not urogenital Ct strains contain mutations in the synthase that abrogate tryptophan synthesis. Here, we discovered that the genomes of serial isolates from a woman with recurrent, treated Ct STIs over many years were identical with a novel synthase mutation. This likely allowed long-term in vivo persistence where active infection resumed only when tryptophan became available. Our findings indicate an emerging adaptive host-pathogen evolutionary strategy for survival in the urogenital tract that will prompt the field to further explore chlamydial persistence, evaluate the genetics of mutant Ct strains and fitness within the host, and their implications for disease pathogenesis.Naraporn SomboonnaNoa ZikloThomas E. FerrinJung Hyuk SuhDeborah DeanAmerican Society for MicrobiologyarticleChlamydia trachomatisindoleinterferon gammasexually transmitted infectionstrpAtryptophan synthesisMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chlamydia trachomatis indole interferon gamma sexually transmitted infections trpA tryptophan synthesis Microbiology QR1-502
spellingShingle	Chlamydia trachomatis indole interferon gamma sexually transmitted infections trpA tryptophan synthesis Microbiology QR1-502 Naraporn Somboonna Noa Ziklo Thomas E. Ferrin Jung Hyuk Suh Deborah Dean Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
description	ABSTRACT Clinical persistence of Chlamydia trachomatis (Ct) sexually transmitted infections (STIs) is a major public health concern. In vitro persistence is known to develop through interferon gamma (IFN-γ) induction of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan, an essential amino acid for Ct replication. The organism can recover from persistence by synthesizing tryptophan from indole, a substrate for the enzyme tryptophan synthase. The majority of Ct strains, except for reference strain B/TW-5/OT, contain an operon comprised of α and β subunits that encode TrpA and TrpB, respectively, and form a functional αββα tetramer. However, trpA mutations in ocular Ct strains, which are responsible for the blinding eye disease known as trachoma, abrogate tryptophan synthesis from indole. We examined serial urogenital samples from a woman who had recurrent Ct infections over 4 years despite antibiotic treatment. The Ct isolates from each infection episode were genome sequenced and analyzed for phenotypic, structural, and functional characteristics. All isolates contained identical mutations in trpA and developed aberrant bodies within intracellular inclusions, visualized by transmission electron microscopy, even when supplemented with indole following IFN-γ treatment. Each isolate displayed an altered αββα structure, could not synthesize tryptophan from indole, and had significantly lower trpBA expression but higher intracellular tryptophan levels compared with those of reference Ct strain F/IC-Cal3. Our data indicate that emergent mutations in the tryptophan operon, which were previously thought to be restricted only to ocular Ct strains, likely resulted in in vivo persistence in the described patient and represents a novel host-pathogen adaptive strategy for survival. IMPORTANCE Chlamydia trachomatis (Ct) is the most common sexually transmitted bacterium with more than 131 million cases occurring annually worldwide. Ct infections are often asymptomatic, persisting for many years despite treatment. In vitro recovery from persistence occurs when indole is utilized by the organism’s tryptophan synthase to synthesize tryptophan, an essential amino acid for replication. Ocular but not urogenital Ct strains contain mutations in the synthase that abrogate tryptophan synthesis. Here, we discovered that the genomes of serial isolates from a woman with recurrent, treated Ct STIs over many years were identical with a novel synthase mutation. This likely allowed long-term in vivo persistence where active infection resumed only when tryptophan became available. Our findings indicate an emerging adaptive host-pathogen evolutionary strategy for survival in the urogenital tract that will prompt the field to further explore chlamydial persistence, evaluate the genetics of mutant Ct strains and fitness within the host, and their implications for disease pathogenesis.
format	article
author	Naraporn Somboonna Noa Ziklo Thomas E. Ferrin Jung Hyuk Suh Deborah Dean
author_facet	Naraporn Somboonna Noa Ziklo Thomas E. Ferrin Jung Hyuk Suh Deborah Dean
author_sort	Naraporn Somboonna
title	Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
title_short	Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
title_full	Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
title_fullStr	Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
title_full_unstemmed	Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon
title_sort	clinical persistence of <named-content content-type="genus-species">chlamydia trachomatis</named-content> sexually transmitted strains involves novel mutations in the functional αββα tetramer of the tryptophan synthase operon
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/8e023c33226040bcb3d0601379d86a27
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Clinical Persistence of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Sexually Transmitted Strains Involves Novel Mutations in the Functional αββα Tetramer of the Tryptophan Synthase Operon

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