Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation

ABSTRACT Iron is essential for growth and development of Chlamydia. Its long-term starvation in cultured mammalian cells leads to production of aberrant noninfectious chlamydial forms, also known as persistence. Immediate transcriptional responses to iron limitation have not been characterized, leav...

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Autores principales:	Amanda J. Brinkworth, Mark R. Wildung, Rey A. Carabeo
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Chlamydia microbiology global regulatory networks intracellular bacteria iron reduction stress response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/04001fe98f3c474a9dab3ab1b9a06401
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spelling	oai:doaj.org-article:04001fe98f3c474a9dab3ab1b9a064012021-12-02T19:45:30ZGenomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation10.1128/mSystems.00184-172379-5077https://doaj.org/article/04001fe98f3c474a9dab3ab1b9a064012018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00184-17https://doaj.org/toc/2379-5077ABSTRACT Iron is essential for growth and development of Chlamydia. Its long-term starvation in cultured mammalian cells leads to production of aberrant noninfectious chlamydial forms, also known as persistence. Immediate transcriptional responses to iron limitation have not been characterized, leaving a knowledge gap of how Chlamydia regulates its response to changes in iron availability. We used the fast-chelating agent 2,2′-bipyridyl (BPDL) to homogeneously starve Chlamydia trachomatis serovar L2 of iron, starting at 6 or 12 h postinfection. Immediate transcriptional responses were monitored after only 3 or 6 h of BPDL treatment, well before formation of aberrant Chlamydia. The first genomewide transcriptional response of C. trachomatis to iron starvation was subsequently determined utilizing RNA sequencing. Only 7% and 8% of the genome were differentially expressed in response to iron starvation at the early and middle stages of development, respectively. Biological pathway analysis revealed an overarching theme. Synthesis of macromolecular precursors (deoxynucleotides, amino acids, charged tRNAs, and acetyl coenzyme A [acetyl-CoA]) was upregulated, while energy-expensive processes (ABC transport and translation) were downregulated. A large fraction of differentially downregulated genes are involved in translation, including those encoding ribosome assembly and initiation and termination factors, which could be analogous to the translation downregulation triggered by stress in other prokaryotes during stringent responses. Additionally, transcriptional upregulation of DNA repair, oxidative stress, and tryptophan salvage genes reveals a possible coordination of responses to multiple antimicrobial and immunological insults. These responses of replicative-phase Chlamydia to iron starvation indicate a prioritization of survival over replication, enabling the pathogen to “stock the pantry” with ingredients needed for rapid growth once optimal iron levels are restored. IMPORTANCE By utilizing an experimental approach that monitors the immediate global response of Chlamydia trachomatis to iron starvation, clues to long-standing issues in Chlamydia biology are revealed, including how Chlamydia adapts to this stress. We determined that this pathogen initiates a transcriptional program that prioritizes replenishment of nutrient stores over replication, possibly in preparation for rapid growth once optimal iron levels are restored. Transcription of genes for biosynthesis of metabolic precursors was generally upregulated, while those involved in multiple steps of translation were downregulated. We also observed an increase in transcription of genes involved in DNA repair and neutralizing oxidative stress, indicating that Chlamydia employs an “all-or-nothing” strategy. Its small genome limits its ability to tailor a specific response to a particular stress. Therefore, the “all-or-nothing” strategy may be the most efficient way of surviving within the host, where the pathogen likely encounters multiple simultaneous immunological and nutritional insults.Amanda J. BrinkworthMark R. WildungRey A. CarabeoAmerican Society for MicrobiologyarticleChlamydiamicrobiologyglobal regulatory networksintracellular bacteriairon reductionstress responseMicrobiologyQR1-502ENmSystems, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chlamydia microbiology global regulatory networks intracellular bacteria iron reduction stress response Microbiology QR1-502
spellingShingle	Chlamydia microbiology global regulatory networks intracellular bacteria iron reduction stress response Microbiology QR1-502 Amanda J. Brinkworth Mark R. Wildung Rey A. Carabeo Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
description	ABSTRACT Iron is essential for growth and development of Chlamydia. Its long-term starvation in cultured mammalian cells leads to production of aberrant noninfectious chlamydial forms, also known as persistence. Immediate transcriptional responses to iron limitation have not been characterized, leaving a knowledge gap of how Chlamydia regulates its response to changes in iron availability. We used the fast-chelating agent 2,2′-bipyridyl (BPDL) to homogeneously starve Chlamydia trachomatis serovar L2 of iron, starting at 6 or 12 h postinfection. Immediate transcriptional responses were monitored after only 3 or 6 h of BPDL treatment, well before formation of aberrant Chlamydia. The first genomewide transcriptional response of C. trachomatis to iron starvation was subsequently determined utilizing RNA sequencing. Only 7% and 8% of the genome were differentially expressed in response to iron starvation at the early and middle stages of development, respectively. Biological pathway analysis revealed an overarching theme. Synthesis of macromolecular precursors (deoxynucleotides, amino acids, charged tRNAs, and acetyl coenzyme A [acetyl-CoA]) was upregulated, while energy-expensive processes (ABC transport and translation) were downregulated. A large fraction of differentially downregulated genes are involved in translation, including those encoding ribosome assembly and initiation and termination factors, which could be analogous to the translation downregulation triggered by stress in other prokaryotes during stringent responses. Additionally, transcriptional upregulation of DNA repair, oxidative stress, and tryptophan salvage genes reveals a possible coordination of responses to multiple antimicrobial and immunological insults. These responses of replicative-phase Chlamydia to iron starvation indicate a prioritization of survival over replication, enabling the pathogen to “stock the pantry” with ingredients needed for rapid growth once optimal iron levels are restored. IMPORTANCE By utilizing an experimental approach that monitors the immediate global response of Chlamydia trachomatis to iron starvation, clues to long-standing issues in Chlamydia biology are revealed, including how Chlamydia adapts to this stress. We determined that this pathogen initiates a transcriptional program that prioritizes replenishment of nutrient stores over replication, possibly in preparation for rapid growth once optimal iron levels are restored. Transcription of genes for biosynthesis of metabolic precursors was generally upregulated, while those involved in multiple steps of translation were downregulated. We also observed an increase in transcription of genes involved in DNA repair and neutralizing oxidative stress, indicating that Chlamydia employs an “all-or-nothing” strategy. Its small genome limits its ability to tailor a specific response to a particular stress. Therefore, the “all-or-nothing” strategy may be the most efficient way of surviving within the host, where the pathogen likely encounters multiple simultaneous immunological and nutritional insults.
format	article
author	Amanda J. Brinkworth Mark R. Wildung Rey A. Carabeo
author_facet	Amanda J. Brinkworth Mark R. Wildung Rey A. Carabeo
author_sort	Amanda J. Brinkworth
title	Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
title_short	Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
title_full	Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
title_fullStr	Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
title_full_unstemmed	Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation
title_sort	genomewide transcriptional responses of iron-starved <named-content content-type="genus-species">chlamydia trachomatis</named-content> reveal prioritization of metabolic precursor synthesis over protein translation
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/04001fe98f3c474a9dab3ab1b9a06401
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Genomewide Transcriptional Responses of Iron-Starved <named-content content-type="genus-species">Chlamydia trachomatis</named-content> Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation

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