A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages

ABSTRACT The BvgS/BvgA two-component system controls expression of ∼550 genes of Bordetella pertussis, of which, ∼245 virulence-related genes are positively regulated by the BvgS-phosphorylated transcriptional regulator protein BvgA (BvgA∼P). We found that a single G-to-T nucleotide transversion in...

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Autores principales:	Jakub Novák, David Jurnečka, Irena Linhartová, Jana Holubová, Ondřej Staněk, Daniel Štipl, Ana Dienstbier, Branislav Večerek, Nayara Azevedo, Jan Provazník, Vladimír Beneš, Peter Šebo
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Bordetella pertussis host-pathogen interactions intracellular bacteria macrophages two-component regulatory systems virulence regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cf6ec5a1115a47508d4d8820cec5b491
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spelling	oai:doaj.org-article:cf6ec5a1115a47508d4d8820cec5b4912021-12-02T18:44:44ZA Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages10.1128/mSystems.00612-202379-5077https://doaj.org/article/cf6ec5a1115a47508d4d8820cec5b4912020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00612-20https://doaj.org/toc/2379-5077ABSTRACT The BvgS/BvgA two-component system controls expression of ∼550 genes of Bordetella pertussis, of which, ∼245 virulence-related genes are positively regulated by the BvgS-phosphorylated transcriptional regulator protein BvgA (BvgA∼P). We found that a single G-to-T nucleotide transversion in the 5′-untranslated region (5′-UTR) of the rplN gene enhanced transcription of the ribosomal protein operon and of the rpoA gene and provoked global dysregulation of B. pertussis genome expression. This comprised overproduction of the alpha subunit (RpoA) of the DNA-dependent RNA polymerase, downregulated BvgA and BvgS protein production, and impaired production and secretion of virulence factors by the mutant. Nonetheless, the mutant survived like the parental bacteria for >2 weeks inside infected primary human macrophages and persisted within infected mouse lungs for a longer period than wild-type B. pertussis. These observations suggest that downregulation of virulence factor production by bacteria internalized into host cells may enable persistence of the whooping cough agent in the airways. IMPORTANCE We show that a spontaneous mutation that upregulates transcription of an operon encoding ribosomal proteins and causes overproduction of the downstream-encoded α subunit (RpoA) of RNA polymerase causes global effects on gene expression levels and proteome composition of Bordetella pertussis. Nevertheless, the resulting important downregulation of the BvgAS-controlled expression of virulence factors of the whooping cough agent did not compromise its capacity to persist for prolonged periods inside primary human macrophage cells, and it even enhanced its capacity to persist in infected mouse lungs. These observations suggest that the modulation of BvgAS-controlled expression of virulence factors may occur also during natural infections of human airways by Bordetella pertussis and may possibly account for long-term persistence of the pathogen within infected cells of the airways.Jakub NovákDavid JurnečkaIrena LinhartováJana HolubováOndřej StaněkDaniel ŠtiplAna DienstbierBranislav VečerekNayara AzevedoJan ProvazníkVladimír BenešPeter ŠeboAmerican Society for MicrobiologyarticleBordetella pertussishost-pathogen interactionsintracellular bacteriamacrophagestwo-component regulatory systemsvirulence regulationMicrobiologyQR1-502ENmSystems, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Bordetella pertussis host-pathogen interactions intracellular bacteria macrophages two-component regulatory systems virulence regulation Microbiology QR1-502
spellingShingle	Bordetella pertussis host-pathogen interactions intracellular bacteria macrophages two-component regulatory systems virulence regulation Microbiology QR1-502 Jakub Novák David Jurnečka Irena Linhartová Jana Holubová Ondřej Staněk Daniel Štipl Ana Dienstbier Branislav Večerek Nayara Azevedo Jan Provazník Vladimír Beneš Peter Šebo A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
description	ABSTRACT The BvgS/BvgA two-component system controls expression of ∼550 genes of Bordetella pertussis, of which, ∼245 virulence-related genes are positively regulated by the BvgS-phosphorylated transcriptional regulator protein BvgA (BvgA∼P). We found that a single G-to-T nucleotide transversion in the 5′-untranslated region (5′-UTR) of the rplN gene enhanced transcription of the ribosomal protein operon and of the rpoA gene and provoked global dysregulation of B. pertussis genome expression. This comprised overproduction of the alpha subunit (RpoA) of the DNA-dependent RNA polymerase, downregulated BvgA and BvgS protein production, and impaired production and secretion of virulence factors by the mutant. Nonetheless, the mutant survived like the parental bacteria for >2 weeks inside infected primary human macrophages and persisted within infected mouse lungs for a longer period than wild-type B. pertussis. These observations suggest that downregulation of virulence factor production by bacteria internalized into host cells may enable persistence of the whooping cough agent in the airways. IMPORTANCE We show that a spontaneous mutation that upregulates transcription of an operon encoding ribosomal proteins and causes overproduction of the downstream-encoded α subunit (RpoA) of RNA polymerase causes global effects on gene expression levels and proteome composition of Bordetella pertussis. Nevertheless, the resulting important downregulation of the BvgAS-controlled expression of virulence factors of the whooping cough agent did not compromise its capacity to persist for prolonged periods inside primary human macrophage cells, and it even enhanced its capacity to persist in infected mouse lungs. These observations suggest that the modulation of BvgAS-controlled expression of virulence factors may occur also during natural infections of human airways by Bordetella pertussis and may possibly account for long-term persistence of the pathogen within infected cells of the airways.
format	article
author	Jakub Novák David Jurnečka Irena Linhartová Jana Holubová Ondřej Staněk Daniel Štipl Ana Dienstbier Branislav Večerek Nayara Azevedo Jan Provazník Vladimír Beneš Peter Šebo
author_facet	Jakub Novák David Jurnečka Irena Linhartová Jana Holubová Ondřej Staněk Daniel Štipl Ana Dienstbier Branislav Večerek Nayara Azevedo Jan Provazník Vladimír Beneš Peter Šebo
author_sort	Jakub Novák
title	A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
title_short	A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
title_full	A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
title_fullStr	A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
title_full_unstemmed	A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages
title_sort	mutation upstream of the <italic toggle="yes">rpln-rpsd</italic> ribosomal operon downregulates <named-content content-type="genus-species">bordetella pertussis</named-content> virulence factor production without compromising bacterial survival within human macrophages
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/cf6ec5a1115a47508d4d8820cec5b491
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A Mutation Upstream of the <italic toggle="yes">rplN-rpsD</italic> Ribosomal Operon Downregulates <named-content content-type="genus-species">Bordetella pertussis</named-content> Virulence Factor Production without Compromising Bacterial Survival within Human Macrophages

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