The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>

ABSTRACT The Salmonella cytolethal distending toxin (S-CDT), first described as the “typhoid toxin” in Salmonella enterica subsp. enterica serotype Typhi, induces DNA damage in eukaryotic cells. Recent studies have shown that more than 40 nontyphoidal Salmonella (NTS) serotypes carry genes that enco...

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Autores principales:	Rachel A. Miller, Michael I. Betteken, Xiaodong Guo, Craig Altier, Gerald E. Duhamel, Martin Wiedmann
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	DNA damage Salmonella nontyphoidal typhoid toxin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e1bb783091be41a0bd0d214522588a39
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spelling	oai:doaj.org-article:e1bb783091be41a0bd0d214522588a392021-11-15T15:53:26ZThe Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>10.1128/mBio.00467-182150-7511https://doaj.org/article/e1bb783091be41a0bd0d214522588a392018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00467-18https://doaj.org/toc/2150-7511ABSTRACT The Salmonella cytolethal distending toxin (S-CDT), first described as the “typhoid toxin” in Salmonella enterica subsp. enterica serotype Typhi, induces DNA damage in eukaryotic cells. Recent studies have shown that more than 40 nontyphoidal Salmonella (NTS) serotypes carry genes that encode S-CDT, yet very little is known about the activity, function, and role of S-CDT in NTS. Here we show that deletion of genes encoding the binding subunit (pltB) and a bacteriophage muramidase predicted to play a role in toxin export (ttsA) does not abolish toxin activity in the S-CDT-positive NTS Salmonella enterica subsp. enterica serotype Javiana. However, S. Javiana strains harboring deletions of both pltB and its homolog artB, had a complete loss of S-CDT activity, suggesting that S. Javiana carries genes encoding two variants of the binding subunit. S-CDT-mediated DNA damage, as determined by phosphorylation of histone 2AX (H2AX), producing phosphorylated H2AX (γH2AX), was restricted to epithelial cells in S and G2/M phases of the cell cycle and did not result in apoptosis or cell death. Compared to mice infected with a ΔcdtB strain, mice infected with wild-type S. Javiana had significantly higher levels of S. Javiana in the liver, but not in the spleen, ileum, or cecum. Overall, we show that production of active S-CDT by NTS serotype S. Javiana requires different genes (cdtB, pltA, and either pltB or artB) for expression of biologically active toxin than those reported for S-CDT production by S. Typhi (cdtB, pltA, pltB, and ttsA). However, as in S. Typhi, NTS S-CDT influences the outcome of infection both in vitro and in vivo. IMPORTANCE Nontyphoidal Salmonella (NTS) are a major cause of bacterial food-borne illness worldwide; however, our understanding of virulence mechanisms that determine the outcome and severity of nontyphoidal salmonellosis is incompletely understood. Here we show that S-CDT produced by NTS plays a significant role in the outcome of infection both in vitro and in vivo, highlighting S-CDT as an important virulence factor for nontyphoidal Salmonella serotypes. Our data also contribute novel information about the function of S-CDT, as S-CDT-mediated DNA damage occurs only during certain phases of the cell cycle, and the resulting damage does not induce cell death as assessed using a propidium iodide exclusion assay. Importantly, our data support that, despite having genetically similar S-CDT operons, NTS serotype S. Javiana has different genetic requirements than S. Typhi, for the production and export of active S-CDT.Rachel A. MillerMichael I. BettekenXiaodong GuoCraig AltierGerald E. DuhamelMartin WiedmannAmerican Society for MicrobiologyarticleDNA damageSalmonellanontyphoidaltyphoid toxinMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA damage Salmonella nontyphoidal typhoid toxin Microbiology QR1-502
spellingShingle	DNA damage Salmonella nontyphoidal typhoid toxin Microbiology QR1-502 Rachel A. Miller Michael I. Betteken Xiaodong Guo Craig Altier Gerald E. Duhamel Martin Wiedmann The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
description	ABSTRACT The Salmonella cytolethal distending toxin (S-CDT), first described as the “typhoid toxin” in Salmonella enterica subsp. enterica serotype Typhi, induces DNA damage in eukaryotic cells. Recent studies have shown that more than 40 nontyphoidal Salmonella (NTS) serotypes carry genes that encode S-CDT, yet very little is known about the activity, function, and role of S-CDT in NTS. Here we show that deletion of genes encoding the binding subunit (pltB) and a bacteriophage muramidase predicted to play a role in toxin export (ttsA) does not abolish toxin activity in the S-CDT-positive NTS Salmonella enterica subsp. enterica serotype Javiana. However, S. Javiana strains harboring deletions of both pltB and its homolog artB, had a complete loss of S-CDT activity, suggesting that S. Javiana carries genes encoding two variants of the binding subunit. S-CDT-mediated DNA damage, as determined by phosphorylation of histone 2AX (H2AX), producing phosphorylated H2AX (γH2AX), was restricted to epithelial cells in S and G2/M phases of the cell cycle and did not result in apoptosis or cell death. Compared to mice infected with a ΔcdtB strain, mice infected with wild-type S. Javiana had significantly higher levels of S. Javiana in the liver, but not in the spleen, ileum, or cecum. Overall, we show that production of active S-CDT by NTS serotype S. Javiana requires different genes (cdtB, pltA, and either pltB or artB) for expression of biologically active toxin than those reported for S-CDT production by S. Typhi (cdtB, pltA, pltB, and ttsA). However, as in S. Typhi, NTS S-CDT influences the outcome of infection both in vitro and in vivo. IMPORTANCE Nontyphoidal Salmonella (NTS) are a major cause of bacterial food-borne illness worldwide; however, our understanding of virulence mechanisms that determine the outcome and severity of nontyphoidal salmonellosis is incompletely understood. Here we show that S-CDT produced by NTS plays a significant role in the outcome of infection both in vitro and in vivo, highlighting S-CDT as an important virulence factor for nontyphoidal Salmonella serotypes. Our data also contribute novel information about the function of S-CDT, as S-CDT-mediated DNA damage occurs only during certain phases of the cell cycle, and the resulting damage does not induce cell death as assessed using a propidium iodide exclusion assay. Importantly, our data support that, despite having genetically similar S-CDT operons, NTS serotype S. Javiana has different genetic requirements than S. Typhi, for the production and export of active S-CDT.
format	article
author	Rachel A. Miller Michael I. Betteken Xiaodong Guo Craig Altier Gerald E. Duhamel Martin Wiedmann
author_facet	Rachel A. Miller Michael I. Betteken Xiaodong Guo Craig Altier Gerald E. Duhamel Martin Wiedmann
author_sort	Rachel A. Miller
title	The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
title_short	The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
title_full	The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
title_fullStr	The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
title_full_unstemmed	The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>
title_sort	typhoid toxin produced by the nontyphoidal <italic toggle="yes">salmonella enterica</italic> serotype javiana is required for induction of a dna damage response <italic toggle="yes">in vitro</italic> and systemic spread <italic toggle="yes">in vivo</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/e1bb783091be41a0bd0d214522588a39
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The Typhoid Toxin Produced by the Nontyphoidal <italic toggle="yes">Salmonella enterica</italic> Serotype Javiana Is Required for Induction of a DNA Damage Response <italic toggle="yes">In Vitro</italic> and Systemic Spread <italic toggle="yes">In Vivo</italic>

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