Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut

ABSTRACT Elimination or alteration of select members of the gut microbiota is key to therapeutic efficacy. However, the complexity of these microbial inhabitants makes it challenging to precisely target bacteria. Here, we deliver exogenous genes to specific bacteria by genomic integration of tempera...

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Autores principales:	Bryan B. Hsu, Jeffrey C. Way, Pamela A. Silver
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Shiga toxin bacteriophage microbiome antivirulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d09bd6d5772b4350946f7492476d8b08
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spelling	oai:doaj.org-article:d09bd6d5772b4350946f7492476d8b082021-12-02T18:39:47ZStable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut10.1128/mSystems.00013-202379-5077https://doaj.org/article/d09bd6d5772b4350946f7492476d8b082020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00013-20https://doaj.org/toc/2379-5077ABSTRACT Elimination or alteration of select members of the gut microbiota is key to therapeutic efficacy. However, the complexity of these microbial inhabitants makes it challenging to precisely target bacteria. Here, we deliver exogenous genes to specific bacteria by genomic integration of temperate phage for long-lasting modification. As a real-world therapeutic test, we engineered λ phage to transcriptionally repress Shiga toxin by using genetic hybrids between λ and other lambdoid phages to overcome resistance encoded by the virulence-expressing prophage. We show that a single dose of engineered phage propagates throughout the bacterial community and reduces Shiga toxin production in an enteric mouse model of infection without markedly affecting bacterial concentrations. Our work reveals a new framework for transferring functions to bacteria within their native environment. IMPORTANCE With the increasing frequency of antibiotic resistance, it is critical to explore new therapeutic strategies for treating bacterial infections. Here, we use a temperate phage, i.e., one that integrates itself into the bacterial genome, to neutralize the expression of a virulence factor by modifying bacterial function at the genetic level. We show that Shiga toxin production can be significantly reduced in vitro and in the mammalian gut. Alternative to traditional applications of phage therapy that rely on killing bacteria, our genetics-based antivirulence approach introduces a new framework for treating bacterial infections.Bryan B. HsuJeffrey C. WayPamela A. SilverAmerican Society for MicrobiologyarticleShiga toxinbacteriophagemicrobiomeantivirulenceMicrobiologyQR1-502ENmSystems, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Shiga toxin bacteriophage microbiome antivirulence Microbiology QR1-502
spellingShingle	Shiga toxin bacteriophage microbiome antivirulence Microbiology QR1-502 Bryan B. Hsu Jeffrey C. Way Pamela A. Silver Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
description	ABSTRACT Elimination or alteration of select members of the gut microbiota is key to therapeutic efficacy. However, the complexity of these microbial inhabitants makes it challenging to precisely target bacteria. Here, we deliver exogenous genes to specific bacteria by genomic integration of temperate phage for long-lasting modification. As a real-world therapeutic test, we engineered λ phage to transcriptionally repress Shiga toxin by using genetic hybrids between λ and other lambdoid phages to overcome resistance encoded by the virulence-expressing prophage. We show that a single dose of engineered phage propagates throughout the bacterial community and reduces Shiga toxin production in an enteric mouse model of infection without markedly affecting bacterial concentrations. Our work reveals a new framework for transferring functions to bacteria within their native environment. IMPORTANCE With the increasing frequency of antibiotic resistance, it is critical to explore new therapeutic strategies for treating bacterial infections. Here, we use a temperate phage, i.e., one that integrates itself into the bacterial genome, to neutralize the expression of a virulence factor by modifying bacterial function at the genetic level. We show that Shiga toxin production can be significantly reduced in vitro and in the mammalian gut. Alternative to traditional applications of phage therapy that rely on killing bacteria, our genetics-based antivirulence approach introduces a new framework for treating bacterial infections.
format	article
author	Bryan B. Hsu Jeffrey C. Way Pamela A. Silver
author_facet	Bryan B. Hsu Jeffrey C. Way Pamela A. Silver
author_sort	Bryan B. Hsu
title	Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
title_short	Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
title_full	Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
title_fullStr	Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
title_full_unstemmed	Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut
title_sort	stable neutralization of a virulence factor in bacteria using temperate phage in the mammalian gut
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/d09bd6d5772b4350946f7492476d8b08
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Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut

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