Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells

ABSTRACT Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still unce...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ludovico P. Sepe, Kimberly Hartl, Amina Iftekhar, Hilmar Berger, Naveen Kumar, Christian Goosmann, Sascha Chopra, Sven Christian Schmidt, Rajendra Kumar Gurumurthy, Thomas F. Meyer, Francesco Boccellato
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	DNA damage gallbladder mucosoid cultures organoid cultures Salmonella typhoid toxin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1ae6b72acc6640248948774430ee9160
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1ae6b72acc6640248948774430ee9160
record_format	dspace
spelling	oai:doaj.org-article:1ae6b72acc6640248948774430ee91602021-11-15T16:19:09ZGenotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells10.1128/mBio.01911-202150-7511https://doaj.org/article/1ae6b72acc6640248948774430ee91602020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01911-20https://doaj.org/toc/2150-7511ABSTRACT Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC. IMPORTANCE Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the role of bacterial genotoxins has become more relevant. Salmonella enterica serovars Typhi and Paratyphi A have been clinically associated with gallbladder cancer. By harnessing the stem cell potential of cells from healthy human gallbladder explant, we regenerated and propagated the epithelium of this organ in vitro and used these cultures to model S. Paratyphi A infection. This study demonstrates the importance of the typhoid toxin, encoded only by these specific serovars, in causing genomic instability in healthy gallbladder cells, posing intoxicated cells at risk of malignant transformation.Ludovico P. SepeKimberly HartlAmina IftekharHilmar BergerNaveen KumarChristian GoosmannSascha ChopraSven Christian SchmidtRajendra Kumar GurumurthyThomas F. MeyerFrancesco BoccellatoAmerican Society for MicrobiologyarticleDNA damagegallbladdermucosoid culturesorganoid culturesSalmonellatyphoid toxinMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA damage gallbladder mucosoid cultures organoid cultures Salmonella typhoid toxin Microbiology QR1-502
spellingShingle	DNA damage gallbladder mucosoid cultures organoid cultures Salmonella typhoid toxin Microbiology QR1-502 Ludovico P. Sepe Kimberly Hartl Amina Iftekhar Hilmar Berger Naveen Kumar Christian Goosmann Sascha Chopra Sven Christian Schmidt Rajendra Kumar Gurumurthy Thomas F. Meyer Francesco Boccellato Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
description	ABSTRACT Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC. IMPORTANCE Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the role of bacterial genotoxins has become more relevant. Salmonella enterica serovars Typhi and Paratyphi A have been clinically associated with gallbladder cancer. By harnessing the stem cell potential of cells from healthy human gallbladder explant, we regenerated and propagated the epithelium of this organ in vitro and used these cultures to model S. Paratyphi A infection. This study demonstrates the importance of the typhoid toxin, encoded only by these specific serovars, in causing genomic instability in healthy gallbladder cells, posing intoxicated cells at risk of malignant transformation.
format	article
author	Ludovico P. Sepe Kimberly Hartl Amina Iftekhar Hilmar Berger Naveen Kumar Christian Goosmann Sascha Chopra Sven Christian Schmidt Rajendra Kumar Gurumurthy Thomas F. Meyer Francesco Boccellato
author_facet	Ludovico P. Sepe Kimberly Hartl Amina Iftekhar Hilmar Berger Naveen Kumar Christian Goosmann Sascha Chopra Sven Christian Schmidt Rajendra Kumar Gurumurthy Thomas F. Meyer Francesco Boccellato
author_sort	Ludovico P. Sepe
title	Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
title_short	Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
title_full	Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
title_fullStr	Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
title_full_unstemmed	Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells
title_sort	genotoxic effect of <italic toggle="yes">salmonella</italic> paratyphi a infection on human primary gallbladder cells
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/1ae6b72acc6640248948774430ee9160
work_keys_str_mv	AT ludovicopsepe genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT kimberlyhartl genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT aminaiftekhar genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT hilmarberger genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT naveenkumar genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT christiangoosmann genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT saschachopra genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT svenchristianschmidt genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT rajendrakumargurumurthy genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT thomasfmeyer genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells AT francescoboccellato genotoxiceffectofitalictoggleyessalmonellaitalicparatyphiainfectiononhumanprimarygallbladdercells
_version_	1718426890015866880

Genotoxic Effect of <italic toggle="yes">Salmonella</italic> Paratyphi A Infection on Human Primary Gallbladder Cells

Ejemplares similares