New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions

ABSTRACT Only a few, relatively cumbersome animal models enable long-term Gram-negative bacterial infections that mimic human situations, where untreated infections can last for weeks. Here, we describe a simple murine cutaneous abscess model that enables chronic or progressive infections, depending...

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Autores principales:	Daniel Pletzer, Sarah C. Mansour, Kelli Wuerth, Negin Rahanjam, Robert E. W. Hancock
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/53fda5d510254148b4e905a114d170d6
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spelling	oai:doaj.org-article:53fda5d510254148b4e905a114d170d62021-11-15T15:51:07ZNew Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions10.1128/mBio.00140-172150-7511https://doaj.org/article/53fda5d510254148b4e905a114d170d62017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00140-17https://doaj.org/toc/2150-7511ABSTRACT Only a few, relatively cumbersome animal models enable long-term Gram-negative bacterial infections that mimic human situations, where untreated infections can last for weeks. Here, we describe a simple murine cutaneous abscess model that enables chronic or progressive infections, depending on the subcutaneously injected bacterial strain. In this model, Pseudomonas aeruginosa cystic fibrosis epidemic isolate LESB58 caused localized high-density skin and soft tissue infections and necrotic skin lesions for up to 10 days but did not disseminate in either CD-1 or C57BL/6 mice. The model was adapted for use with four major Gram-negative nosocomial pathogens, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, and Escherichia coli. This model enabled noninvasive imaging and tracking of lux-tagged bacteria, the influx of activated neutrophils, and production of reactive oxygen-nitrogen species at the infection site. Screening antimicrobials against high-density infections showed that local but not intravenous administration of gentamicin, ciprofloxacin, and meropenem significantly but incompletely reduced bacterial counts and superficial tissue dermonecrosis. Bacterial RNA isolated from the abscess tissue revealed that Pseudomonas genes involved in iron uptake, toxin production, surface lipopolysaccharide regulation, adherence, and lipase production were highly upregulated whereas phenazine production and expression of global activator gacA were downregulated. The model was validated for studying virulence using mutants of more-virulent P. aeruginosa strain PA14. Thus, mutants defective in flagella or motility, type III secretion, or siderophore biosynthesis were noninvasive and suppressed dermal necrosis in mice, while a strain with a mutation in the bfiS gene encoding a sensor kinase showed enhanced invasiveness and mortality in mice compared to controls infected with wild-type P. aeruginosa PA14. IMPORTANCE More than two-thirds of hospital infections are chronic or high-density biofilm infections and difficult to treat due to adaptive, multidrug resistance. Unfortunately, current models of chronic infection are technically challenging and difficult to track without sacrificing animals. Here we describe a model of chronic subcutaneous infection and abscess formation by medically important nosocomial Gram-negative pathogens that is simple and can be used for tracking infections by imaging, examining pathology and immune responses, testing antimicrobial treatments suitable for high-density bacterial infections, and studying virulence. We propose that this mouse model can be a game changer for modeling hard-to-treat Gram-negative bacterial chronic and skin infections.Daniel PletzerSarah C. MansourKelli WuerthNegin RahanjamRobert E. W. HancockAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Daniel Pletzer Sarah C. Mansour Kelli Wuerth Negin Rahanjam Robert E. W. Hancock New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
description	ABSTRACT Only a few, relatively cumbersome animal models enable long-term Gram-negative bacterial infections that mimic human situations, where untreated infections can last for weeks. Here, we describe a simple murine cutaneous abscess model that enables chronic or progressive infections, depending on the subcutaneously injected bacterial strain. In this model, Pseudomonas aeruginosa cystic fibrosis epidemic isolate LESB58 caused localized high-density skin and soft tissue infections and necrotic skin lesions for up to 10 days but did not disseminate in either CD-1 or C57BL/6 mice. The model was adapted for use with four major Gram-negative nosocomial pathogens, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, and Escherichia coli. This model enabled noninvasive imaging and tracking of lux-tagged bacteria, the influx of activated neutrophils, and production of reactive oxygen-nitrogen species at the infection site. Screening antimicrobials against high-density infections showed that local but not intravenous administration of gentamicin, ciprofloxacin, and meropenem significantly but incompletely reduced bacterial counts and superficial tissue dermonecrosis. Bacterial RNA isolated from the abscess tissue revealed that Pseudomonas genes involved in iron uptake, toxin production, surface lipopolysaccharide regulation, adherence, and lipase production were highly upregulated whereas phenazine production and expression of global activator gacA were downregulated. The model was validated for studying virulence using mutants of more-virulent P. aeruginosa strain PA14. Thus, mutants defective in flagella or motility, type III secretion, or siderophore biosynthesis were noninvasive and suppressed dermal necrosis in mice, while a strain with a mutation in the bfiS gene encoding a sensor kinase showed enhanced invasiveness and mortality in mice compared to controls infected with wild-type P. aeruginosa PA14. IMPORTANCE More than two-thirds of hospital infections are chronic or high-density biofilm infections and difficult to treat due to adaptive, multidrug resistance. Unfortunately, current models of chronic infection are technically challenging and difficult to track without sacrificing animals. Here we describe a model of chronic subcutaneous infection and abscess formation by medically important nosocomial Gram-negative pathogens that is simple and can be used for tracking infections by imaging, examining pathology and immune responses, testing antimicrobial treatments suitable for high-density bacterial infections, and studying virulence. We propose that this mouse model can be a game changer for modeling hard-to-treat Gram-negative bacterial chronic and skin infections.
format	article
author	Daniel Pletzer Sarah C. Mansour Kelli Wuerth Negin Rahanjam Robert E. W. Hancock
author_facet	Daniel Pletzer Sarah C. Mansour Kelli Wuerth Negin Rahanjam Robert E. W. Hancock
author_sort	Daniel Pletzer
title	New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
title_short	New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
title_full	New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
title_fullStr	New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
title_full_unstemmed	New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions
title_sort	new mouse model for chronic infections by gram-negative bacteria enabling the study of anti-infective efficacy and host-microbe interactions
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/53fda5d510254148b4e905a114d170d6
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New Mouse Model for Chronic Infections by Gram-Negative Bacteria Enabling the Study of Anti-Infective Efficacy and Host-Microbe Interactions

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