An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection

ABSTRACT A major obstacle in infection biology is the limited ability to recapitulate human disease trajectories in traditional cell culture and animal models, which impedes the translation of basic research into clinics. Here, we introduce a three-dimensional (3D) intestinal tissue model to study h...

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Autores principales:	Leon N. Schulte, Matthias Schweinlin, Alexander J. Westermann, Harshavardhan Janga, Sara C. Santos, Silke Appenzeller, Heike Walles, Jörg Vogel, Marco Metzger
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Salmonella gene expression infectious disease Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/30c18c5282c4450394907a88f277e373
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spelling	oai:doaj.org-article:30c18c5282c4450394907a88f277e3732021-11-15T15:56:58ZAn Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection10.1128/mBio.03348-192150-7511https://doaj.org/article/30c18c5282c4450394907a88f277e3732020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03348-19https://doaj.org/toc/2150-7511ABSTRACT A major obstacle in infection biology is the limited ability to recapitulate human disease trajectories in traditional cell culture and animal models, which impedes the translation of basic research into clinics. Here, we introduce a three-dimensional (3D) intestinal tissue model to study human enteric infections at a level of detail that is not achieved by conventional two-dimensional monocultures. Our model comprises epithelial and endothelial layers, a primary intestinal collagen scaffold, and immune cells. Upon Salmonella infection, the model mimics human gastroenteritis, in that it restricts the pathogen to the epithelial compartment, an advantage over existing mouse models. Application of dual transcriptome sequencing to the Salmonella-infected model revealed the communication of epithelial, endothelial, monocytic, and natural killer cells among each other and with the pathogen. Our results suggest that Salmonella uses its type III secretion systems to manipulate STAT3-dependent inflammatory responses locally in the epithelium without accompanying alterations in the endothelial compartment. Our approach promises to reveal further human-specific infection strategies employed by Salmonella and other pathogens. IMPORTANCE Infection research routinely employs in vitro cell cultures or in vivo mouse models as surrogates of human hosts. Differences between murine and human immunity and the low level of complexity of traditional cell cultures, however, highlight the demand for alternative models that combine the in vivo-like properties of the human system with straightforward experimental perturbation. Here, we introduce a 3D tissue model comprising multiple cell types of the human intestinal barrier, a primary site of pathogen attack. During infection with the foodborne pathogen Salmonella enterica serovar Typhimurium, our model recapitulates human disease aspects, including pathogen restriction to the epithelial compartment, thereby deviating from the systemic infection in mice. Combination of our model with state-of-the-art genetics revealed Salmonella-mediated local manipulations of human immune responses, likely contributing to the establishment of the pathogen’s infection niche. We propose the adoption of similar 3D tissue models to infection biology, to advance our understanding of molecular infection strategies employed by bacterial pathogens in their human host.Leon N. SchulteMatthias SchweinlinAlexander J. WestermannHarshavardhan JangaSara C. SantosSilke AppenzellerHeike WallesJörg VogelMarco MetzgerAmerican Society for MicrobiologyarticleSalmonellagene expressioninfectious diseaseMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Salmonella gene expression infectious disease Microbiology QR1-502
spellingShingle	Salmonella gene expression infectious disease Microbiology QR1-502 Leon N. Schulte Matthias Schweinlin Alexander J. Westermann Harshavardhan Janga Sara C. Santos Silke Appenzeller Heike Walles Jörg Vogel Marco Metzger An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
description	ABSTRACT A major obstacle in infection biology is the limited ability to recapitulate human disease trajectories in traditional cell culture and animal models, which impedes the translation of basic research into clinics. Here, we introduce a three-dimensional (3D) intestinal tissue model to study human enteric infections at a level of detail that is not achieved by conventional two-dimensional monocultures. Our model comprises epithelial and endothelial layers, a primary intestinal collagen scaffold, and immune cells. Upon Salmonella infection, the model mimics human gastroenteritis, in that it restricts the pathogen to the epithelial compartment, an advantage over existing mouse models. Application of dual transcriptome sequencing to the Salmonella-infected model revealed the communication of epithelial, endothelial, monocytic, and natural killer cells among each other and with the pathogen. Our results suggest that Salmonella uses its type III secretion systems to manipulate STAT3-dependent inflammatory responses locally in the epithelium without accompanying alterations in the endothelial compartment. Our approach promises to reveal further human-specific infection strategies employed by Salmonella and other pathogens. IMPORTANCE Infection research routinely employs in vitro cell cultures or in vivo mouse models as surrogates of human hosts. Differences between murine and human immunity and the low level of complexity of traditional cell cultures, however, highlight the demand for alternative models that combine the in vivo-like properties of the human system with straightforward experimental perturbation. Here, we introduce a 3D tissue model comprising multiple cell types of the human intestinal barrier, a primary site of pathogen attack. During infection with the foodborne pathogen Salmonella enterica serovar Typhimurium, our model recapitulates human disease aspects, including pathogen restriction to the epithelial compartment, thereby deviating from the systemic infection in mice. Combination of our model with state-of-the-art genetics revealed Salmonella-mediated local manipulations of human immune responses, likely contributing to the establishment of the pathogen’s infection niche. We propose the adoption of similar 3D tissue models to infection biology, to advance our understanding of molecular infection strategies employed by bacterial pathogens in their human host.
format	article
author	Leon N. Schulte Matthias Schweinlin Alexander J. Westermann Harshavardhan Janga Sara C. Santos Silke Appenzeller Heike Walles Jörg Vogel Marco Metzger
author_facet	Leon N. Schulte Matthias Schweinlin Alexander J. Westermann Harshavardhan Janga Sara C. Santos Silke Appenzeller Heike Walles Jörg Vogel Marco Metzger
author_sort	Leon N. Schulte
title	An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
title_short	An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
title_full	An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
title_fullStr	An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
title_full_unstemmed	An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection
title_sort	advanced human intestinal coculture model reveals compartmentalized host and pathogen strategies during <italic toggle="yes">salmonella</italic> infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/30c18c5282c4450394907a88f277e373
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An Advanced Human Intestinal Coculture Model Reveals Compartmentalized Host and Pathogen Strategies during <italic toggle="yes">Salmonella</italic> Infection

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