<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence

ABSTRACT ToxR is a major virulence gene regulator in Vibrio cholerae. Although constitutively expressed under many laboratory conditions, our previous work demonstrated that the level of ToxR increases significantly when cells are grown in the presence of the 4 amino acids asparagine, arginine, glut...

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Autores principales:	Alexandra R. Mey, Heidi A. Butz, Shelley M. Payne
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0f1ba24810cc4129ac548b30079e17db
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spelling	oai:doaj.org-article:0f1ba24810cc4129ac548b30079e17db2021-11-15T15:41:26Z<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence10.1128/mBio.01064-152150-7511https://doaj.org/article/0f1ba24810cc4129ac548b30079e17db2015-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01064-15https://doaj.org/toc/2150-7511ABSTRACT ToxR is a major virulence gene regulator in Vibrio cholerae. Although constitutively expressed under many laboratory conditions, our previous work demonstrated that the level of ToxR increases significantly when cells are grown in the presence of the 4 amino acids asparagine, arginine, glutamate, and serine (NRES). We show here that the increase in ToxR production in response to NRES requires the Var/Csr global regulatory circuit. The VarS/VarA two-component system controls the amount of active CsrA, a small RNA-binding protein involved in the regulation of a wide range of cellular processes. Our data show that a varA mutant, which is expected to overproduce active CsrA, had elevated levels of ToxR in the absence of the NRES stimulus. Conversely, specific amino acid substitutions in CsrA were associated with defects in ToxR production in response to NRES. These data indicate that CsrA is a positive regulator of ToxR levels. Unlike previously described effects of CsrA on virulence gene regulation, the effects of CsrA on ToxR were not mediated through quorum sensing and HapR. CsrA is likely essential in V. cholerae, since a complete deletion of csrA was not possible; however, point mutations in CsrA were tolerated well. The CsrA Arg6His mutant had wild-type growth in vitro but was severely attenuated in the infant mouse model of V. cholerae infection, showing that CsrA is critical for pathogenesis. This study has broad implications for our understanding of how V. cholerae integrates its response to environmental cues with the regulation of important virulence genes. IMPORTANCE In order to colonize the human host, Vibrio cholerae must sense and respond to environmental signals to ensure appropriate expression of genes required for pathogenesis. Uncovering how V. cholerae senses its environment and activates its virulence gene repertoire is critical for our understanding of how V. cholerae transitions from its natural aquatic habitat to the human host. Here we demonstrate a previously unknown link between the global regulator CsrA and the major V. cholerae virulence gene regulator ToxR. The role of CsrA in the cell is to receive input from the environment and coordinate an appropriate cellular response. By linking environmental sensing to the ToxR regulon, CsrA effectively acts as a switch that controls pathogenesis in response to specific signals. We demonstrate that CsrA is critical for virulence in the infant mouse model of V. cholerae infection, consistent with its role as an in vivo regulator of virulence gene expression.Alexandra R. MeyHeidi A. ButzShelley M. PayneAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 4 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Alexandra R. Mey Heidi A. Butz Shelley M. Payne <named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
description	ABSTRACT ToxR is a major virulence gene regulator in Vibrio cholerae. Although constitutively expressed under many laboratory conditions, our previous work demonstrated that the level of ToxR increases significantly when cells are grown in the presence of the 4 amino acids asparagine, arginine, glutamate, and serine (NRES). We show here that the increase in ToxR production in response to NRES requires the Var/Csr global regulatory circuit. The VarS/VarA two-component system controls the amount of active CsrA, a small RNA-binding protein involved in the regulation of a wide range of cellular processes. Our data show that a varA mutant, which is expected to overproduce active CsrA, had elevated levels of ToxR in the absence of the NRES stimulus. Conversely, specific amino acid substitutions in CsrA were associated with defects in ToxR production in response to NRES. These data indicate that CsrA is a positive regulator of ToxR levels. Unlike previously described effects of CsrA on virulence gene regulation, the effects of CsrA on ToxR were not mediated through quorum sensing and HapR. CsrA is likely essential in V. cholerae, since a complete deletion of csrA was not possible; however, point mutations in CsrA were tolerated well. The CsrA Arg6His mutant had wild-type growth in vitro but was severely attenuated in the infant mouse model of V. cholerae infection, showing that CsrA is critical for pathogenesis. This study has broad implications for our understanding of how V. cholerae integrates its response to environmental cues with the regulation of important virulence genes. IMPORTANCE In order to colonize the human host, Vibrio cholerae must sense and respond to environmental signals to ensure appropriate expression of genes required for pathogenesis. Uncovering how V. cholerae senses its environment and activates its virulence gene repertoire is critical for our understanding of how V. cholerae transitions from its natural aquatic habitat to the human host. Here we demonstrate a previously unknown link between the global regulator CsrA and the major V. cholerae virulence gene regulator ToxR. The role of CsrA in the cell is to receive input from the environment and coordinate an appropriate cellular response. By linking environmental sensing to the ToxR regulon, CsrA effectively acts as a switch that controls pathogenesis in response to specific signals. We demonstrate that CsrA is critical for virulence in the infant mouse model of V. cholerae infection, consistent with its role as an in vivo regulator of virulence gene expression.
format	article
author	Alexandra R. Mey Heidi A. Butz Shelley M. Payne
author_facet	Alexandra R. Mey Heidi A. Butz Shelley M. Payne
author_sort	Alexandra R. Mey
title	<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
title_short	<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
title_full	<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
title_fullStr	<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
title_full_unstemmed	<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence
title_sort	<named-content content-type="genus-species">vibrio cholerae</named-content> csra regulates toxr levels in response to amino acids and is essential for virulence
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/0f1ba24810cc4129ac548b30079e17db
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<named-content content-type="genus-species">Vibrio cholerae</named-content> CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence

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