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Bacterial Infections

Scnn1b-Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung

Kristen J. Brao, Brendan P. Wille, Joshua Lieberman, Robert K. Ernst, Mark E. Shirtliff, Janette M. Harro
Manuela Raffatellu, Editor
Kristen J. Brao
aDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA
bDepartment of Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Brendan P. Wille
aDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA
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Joshua Lieberman
cDivision of Microbiology, Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
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Robert K. Ernst
aDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA
bDepartment of Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Mark E. Shirtliff
aDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA
bDepartment of Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Janette M. Harro
aDepartment of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA
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Manuela Raffatellu
University of California San Diego School of Medicine
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DOI: 10.1128/IAI.00237-20
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ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. P. aeruginosa lung infections are difficult to treat because P. aeruginosa adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of P. aeruginosa, modeling P. aeruginosa infections in CF has been challenging. Here, we characterize Scnn1b-transgenic (Tg) BALB/c mice as P. aeruginosa lung infection models. Scnn1b-Tg mice overexpress the epithelial Na+ channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected Scnn1b-Tg mice and wild-type littermates with the laboratory P. aeruginosa strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. Scnn1b-Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; Scnn1b-Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. Scnn1b-Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected Scnn1b-Tg mice. In contrast, Scnn1b-Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1β (IL-1β), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of Scnn1b-Tg mice as models of early P. aeruginosa colonization in the CF lung.

FOOTNOTES

    • Received 23 April 2020.
    • Returned for modification 17 June 2020.
    • Accepted 30 June 2020.
    • Accepted manuscript posted online 6 July 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Scnn1b-Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung
Kristen J. Brao, Brendan P. Wille, Joshua Lieberman, Robert K. Ernst, Mark E. Shirtliff, Janette M. Harro
Infection and Immunity Aug 2020, 88 (9) e00237-20; DOI: 10.1128/IAI.00237-20

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Scnn1b-Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung
Kristen J. Brao, Brendan P. Wille, Joshua Lieberman, Robert K. Ernst, Mark E. Shirtliff, Janette M. Harro
Infection and Immunity Aug 2020, 88 (9) e00237-20; DOI: 10.1128/IAI.00237-20
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KEYWORDS

Pseudomonas aeruginosa
cystic fibrosis
mouse model

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