The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi

ABSTRACT Select nontyphoidal Salmonella enterica (NTS) serotypes were recently found to encode the Salmonella cytolethal distending toxin (S-CDT), an important virulence factor for serotype Typhi, the causative agent of typhoid fever. Using a PCR-based assay, we determined that among 21 NTS serotype...

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Autores principales:	Rachel A. Miller, Martin Wiedmann
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/574e27a25a95489a860eb85bb4153e3a
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spelling	oai:doaj.org-article:574e27a25a95489a860eb85bb4153e3a2021-11-15T15:50:16ZThe Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi10.1128/mBio.02109-162150-7511https://doaj.org/article/574e27a25a95489a860eb85bb4153e3a2016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02109-16https://doaj.org/toc/2150-7511ABSTRACT Select nontyphoidal Salmonella enterica (NTS) serotypes were recently found to encode the Salmonella cytolethal distending toxin (S-CDT), an important virulence factor for serotype Typhi, the causative agent of typhoid fever. Using a PCR-based assay, we determined that among 21 NTS serotypes causing the majority of food-borne salmonellosis cases in the United States, genes encoding S-CDT are conserved in isolates representing serotypes Javiana, Montevideo, and Oranienburg but that among serotype Mississippi isolates, the presence of S-CDT-encoding genes is clade associated. HeLa cells infected with representative strains of these S-CDT-positive serotypes had a significantly higher proportion of cells arrested in the G2/M phase than HeLa cells infected with representative strains of S-CDT-negative serotypes Typhimurium, Newport, and Enteritidis. The G2/M cell cycle arrest was dependent on CdtB, the active subunit of S-CDT, as infection with isogenic ΔcdtB mutants abolished their ability to induce a G2/M cell cycle arrest. Infection with S-CDT-encoding serotypes was significantly associated with activation of the host cell’s DNA damage response (DDR), a signaling cascade that is important for detecting and repairing damaged DNA. HeLa cell populations infected with S-CDT-positive serotypes had a significantly higher proportion of cells with DDR protein 53BP1 and γH2AX foci than cells infected with either S-CDT-negative serotypes or isogenic ΔcdtB strains. Intoxication with S-CDT occurred via autocrine and paracrine pathways, as uninfected HeLa cells among populations of infected cells also had an activated DDR. Overall, we show that S-CDT plays a significant role in the cellular outcome of infection with NTS serotypes. IMPORTANCE The recent discovery that multiple serotypes encode S-CDT, which was previously established as an important virulence factor for serotype Typhi, suggested that this toxin may also contribute to the outcome of infection with nontyphoidal serotypes. In this study, we demonstrate that at a cellular level, S-CDT significantly alters the outcome of infection by inducing DNA damage which is associated with a cell cycle arrest and activation of the host cell’s DDR. Importantly, these results contribute valuable information for assessing the public health implications of S-CDT in infections with NTS serotypes. Our data suggest that infection with Salmonella strains that encode S-CDT has the potential to result in DNA damage, which may contribute to long-term sequelae.Rachel A. MillerMartin WiedmannAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Rachel A. Miller Martin Wiedmann The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
description	ABSTRACT Select nontyphoidal Salmonella enterica (NTS) serotypes were recently found to encode the Salmonella cytolethal distending toxin (S-CDT), an important virulence factor for serotype Typhi, the causative agent of typhoid fever. Using a PCR-based assay, we determined that among 21 NTS serotypes causing the majority of food-borne salmonellosis cases in the United States, genes encoding S-CDT are conserved in isolates representing serotypes Javiana, Montevideo, and Oranienburg but that among serotype Mississippi isolates, the presence of S-CDT-encoding genes is clade associated. HeLa cells infected with representative strains of these S-CDT-positive serotypes had a significantly higher proportion of cells arrested in the G2/M phase than HeLa cells infected with representative strains of S-CDT-negative serotypes Typhimurium, Newport, and Enteritidis. The G2/M cell cycle arrest was dependent on CdtB, the active subunit of S-CDT, as infection with isogenic ΔcdtB mutants abolished their ability to induce a G2/M cell cycle arrest. Infection with S-CDT-encoding serotypes was significantly associated with activation of the host cell’s DNA damage response (DDR), a signaling cascade that is important for detecting and repairing damaged DNA. HeLa cell populations infected with S-CDT-positive serotypes had a significantly higher proportion of cells with DDR protein 53BP1 and γH2AX foci than cells infected with either S-CDT-negative serotypes or isogenic ΔcdtB strains. Intoxication with S-CDT occurred via autocrine and paracrine pathways, as uninfected HeLa cells among populations of infected cells also had an activated DDR. Overall, we show that S-CDT plays a significant role in the cellular outcome of infection with NTS serotypes. IMPORTANCE The recent discovery that multiple serotypes encode S-CDT, which was previously established as an important virulence factor for serotype Typhi, suggested that this toxin may also contribute to the outcome of infection with nontyphoidal serotypes. In this study, we demonstrate that at a cellular level, S-CDT significantly alters the outcome of infection by inducing DNA damage which is associated with a cell cycle arrest and activation of the host cell’s DDR. Importantly, these results contribute valuable information for assessing the public health implications of S-CDT in infections with NTS serotypes. Our data suggest that infection with Salmonella strains that encode S-CDT has the potential to result in DNA damage, which may contribute to long-term sequelae.
format	article
author	Rachel A. Miller Martin Wiedmann
author_facet	Rachel A. Miller Martin Wiedmann
author_sort	Rachel A. Miller
title	The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
title_short	The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
title_full	The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
title_fullStr	The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
title_full_unstemmed	The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi
title_sort	cytolethal distending toxin produced by nontyphoidal <italic toggle="yes">salmonella</italic> serotypes javiana, montevideo, oranienburg, and mississippi induces dna damage in a manner similar to that of serotype typhi
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/574e27a25a95489a860eb85bb4153e3a
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The Cytolethal Distending Toxin Produced by Nontyphoidal <italic toggle="yes">Salmonella</italic> Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi

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