Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

ABSTRACT In individuals with sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation while the host background is considered the primary variable affecting disease progression and outcome. To study the effects of bacterial strain differences on the maladaptive immune r...

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Autores principales:	Amelia E. Barber, Brittany A. Fleming, Matthew A. Mulvey
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Escherichia coli ExPEC TLR5 bacteremia bloodstream infections cytokine storm Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0514730e635241d3af0a9374beb50f4c
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spelling	oai:doaj.org-article:0514730e635241d3af0a9374beb50f4c2021-11-15T15:21:22ZSimilarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis10.1128/mSphere.00062-162379-5042https://doaj.org/article/0514730e635241d3af0a9374beb50f4c2016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00062-16https://doaj.org/toc/2379-5042ABSTRACT In individuals with sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation while the host background is considered the primary variable affecting disease progression and outcome. To study the effects of bacterial strain differences on the maladaptive immune responses that are induced during sepsis, we employed a novel zebrafish embryo infection model using extraintestinal pathogenic Escherichia coli (ExPEC) isolates. These genetically diverse pathogens are a leading cause of sepsis and are becoming increasingly dangerous because of the rise of multidrug-resistant strains. Zebrafish infected with ExPEC isolates exhibit many of the pathophysiological features seen in septic human patients, including dysregulated inflammatory responses (cytokine storms), tachycardia, endothelial leakage, and progressive edema. However, only a limited subset of ExPEC isolates can trigger a sepsis-like state and death of the host when introduced into the bloodstream. Mirroring the situation in human patients, antibiotic therapy reduced ExPEC titers and improved host survival rates but was only effective within limited time frames that varied, depending on the infecting pathogen. Intriguingly, we find that phylogenetically distant but similarly lethal ExPEC isolates can stimulate markedly different host transcriptional responses, including disparate levels of inflammatory mediators. These differences correlate with the amounts of bacterial flagellin expression during infection, as well as differential activation of Toll-like receptor 5 by discrete flagellar serotypes. Altogether, this work establishes zebrafish as a relevant model of key aspects of human sepsis and highlights the ability of genetically distinct ExPEC isolates to induce divergent host responses independently of baseline host attributes. IMPORTANCE Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In the United States, sepsis due to ExPEC and other pathogens kills well over a quarter of a million people each year and is associated with tremendous health care costs. A high degree of heterogeneity in the signs and symptomology of sepsis makes this disease notoriously difficult to effectively diagnose and manage. Here, using a zebrafish model of sepsis, we find that similarly lethal but genetically distinct ExPEC isolates can elicit notably disparate host responses. These variances are in part due to differences in the levels and types of flagellin that are expressed by the infecting ExPEC strains. A better understanding of the variable impact that bacterial factors like flagellin have on host responses during sepsis could lead to improved diagnostic and therapeutic approaches to these often deadly infections. Podcast: A podcast concerning this article is available.Amelia E. BarberBrittany A. FlemingMatthew A. MulveyAmerican Society for MicrobiologyarticleEscherichia coliExPECTLR5bacteremiabloodstream infectionscytokine stormMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Escherichia coli ExPEC TLR5 bacteremia bloodstream infections cytokine storm Microbiology QR1-502
spellingShingle	Escherichia coli ExPEC TLR5 bacteremia bloodstream infections cytokine storm Microbiology QR1-502 Amelia E. Barber Brittany A. Fleming Matthew A. Mulvey Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
description	ABSTRACT In individuals with sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation while the host background is considered the primary variable affecting disease progression and outcome. To study the effects of bacterial strain differences on the maladaptive immune responses that are induced during sepsis, we employed a novel zebrafish embryo infection model using extraintestinal pathogenic Escherichia coli (ExPEC) isolates. These genetically diverse pathogens are a leading cause of sepsis and are becoming increasingly dangerous because of the rise of multidrug-resistant strains. Zebrafish infected with ExPEC isolates exhibit many of the pathophysiological features seen in septic human patients, including dysregulated inflammatory responses (cytokine storms), tachycardia, endothelial leakage, and progressive edema. However, only a limited subset of ExPEC isolates can trigger a sepsis-like state and death of the host when introduced into the bloodstream. Mirroring the situation in human patients, antibiotic therapy reduced ExPEC titers and improved host survival rates but was only effective within limited time frames that varied, depending on the infecting pathogen. Intriguingly, we find that phylogenetically distant but similarly lethal ExPEC isolates can stimulate markedly different host transcriptional responses, including disparate levels of inflammatory mediators. These differences correlate with the amounts of bacterial flagellin expression during infection, as well as differential activation of Toll-like receptor 5 by discrete flagellar serotypes. Altogether, this work establishes zebrafish as a relevant model of key aspects of human sepsis and highlights the ability of genetically distinct ExPEC isolates to induce divergent host responses independently of baseline host attributes. IMPORTANCE Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In the United States, sepsis due to ExPEC and other pathogens kills well over a quarter of a million people each year and is associated with tremendous health care costs. A high degree of heterogeneity in the signs and symptomology of sepsis makes this disease notoriously difficult to effectively diagnose and manage. Here, using a zebrafish model of sepsis, we find that similarly lethal but genetically distinct ExPEC isolates can elicit notably disparate host responses. These variances are in part due to differences in the levels and types of flagellin that are expressed by the infecting ExPEC strains. A better understanding of the variable impact that bacterial factors like flagellin have on host responses during sepsis could lead to improved diagnostic and therapeutic approaches to these often deadly infections. Podcast: A podcast concerning this article is available.
format	article
author	Amelia E. Barber Brittany A. Fleming Matthew A. Mulvey
author_facet	Amelia E. Barber Brittany A. Fleming Matthew A. Mulvey
author_sort	Amelia E. Barber
title	Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
title_short	Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
title_full	Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
title_fullStr	Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
title_full_unstemmed	Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis
title_sort	similarly lethal strains of extraintestinal pathogenic <named-content content-type="genus-species">escherichia coli</named-content> trigger markedly diverse host responses in a zebrafish model of sepsis
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0514730e635241d3af0a9374beb50f4c
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Similarly Lethal Strains of Extraintestinal Pathogenic <named-content content-type="genus-species">Escherichia coli</named-content> Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

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