Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis

Charles C. Caldwell, Yi Chen, Holly S. Goetzmann, Yonghua Hao, Michael T. Borchers, Daniel J. Hassett, Lisa R. Young, Dmitri Mavrodi, Linda Thomashow, Gee Lau

Research output: Contribution to journalArticle

Abstract

The cystic fibrosis (CF) airway bacterial pathogen Pseudomonas aeruginosa secretes multiple virulence factors. Among these, the redox active exotoxin pyocyanin (PCN) is produced in concentrations up to 100 μmol/L during infection of CF and other bronchiectatic airways. However, the contributions of PCN during infection of bronchiectatic airways are not appreciated. In this study, we demonstrate that PCN is critical for chronic infection in mouse airways and orchestrates adaptive immune responses that mediate lung damage. Wild-type FVBN mice chronically exposed to PCN developed goblet cell hyperplasia and metaplasia, airway fibrosis, and alveolar airspace destruction. Furthermore, after 12 weeks of exposure to PCN, mouse lungs down-regulated the expression of T helper (Th) type 1 cytokines and polarized toward a Th2 response. Cellular analyses indicated that chronic exposure to PCN profoundly increased the lung population of recruited macrophages, CD4+ T cells , and neutrophils responsible for the secretion of these cytokines. PCN-mediated goblet cell hyperplasia and metaplasia required Th2 cytokine signaling through the Stat6 pathway. In summary, this study establishes that PCN is an important P. aeruginosa virulence factor capable of directly inducing pulmonary pathophysiology in mice, consistent with changes observed in CF and other bronchiectasis lungs.

Original languageEnglish (US)
Pages (from-to)2473-2488
Number of pages16
JournalAmerican Journal of Pathology
Volume175
Issue number6
DOIs
StatePublished - Jan 1 2009

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Pyocyanine
Exotoxins
Cystic Fibrosis
Pseudomonas aeruginosa
Lung
Goblet Cells
Metaplasia
Virulence Factors
Cytokines
Hyperplasia
Infection
Bronchiectasis
Adaptive Immunity
Oxidation-Reduction
Neutrophils
Fibrosis
Macrophages
T-Lymphocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Caldwell, C. C., Chen, Y., Goetzmann, H. S., Hao, Y., Borchers, M. T., Hassett, D. J., ... Lau, G. (2009). Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. American Journal of Pathology, 175(6), 2473-2488. https://doi.org/10.2353/ajpath.2009.090166

Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. / Caldwell, Charles C.; Chen, Yi; Goetzmann, Holly S.; Hao, Yonghua; Borchers, Michael T.; Hassett, Daniel J.; Young, Lisa R.; Mavrodi, Dmitri; Thomashow, Linda; Lau, Gee.

In: American Journal of Pathology, Vol. 175, No. 6, 01.01.2009, p. 2473-2488.

Research output: Contribution to journalArticle

Caldwell, CC, Chen, Y, Goetzmann, HS, Hao, Y, Borchers, MT, Hassett, DJ, Young, LR, Mavrodi, D, Thomashow, L & Lau, G 2009, 'Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis', American Journal of Pathology, vol. 175, no. 6, pp. 2473-2488. https://doi.org/10.2353/ajpath.2009.090166
Caldwell CC, Chen Y, Goetzmann HS, Hao Y, Borchers MT, Hassett DJ et al. Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. American Journal of Pathology. 2009 Jan 1;175(6):2473-2488. https://doi.org/10.2353/ajpath.2009.090166
Caldwell, Charles C. ; Chen, Yi ; Goetzmann, Holly S. ; Hao, Yonghua ; Borchers, Michael T. ; Hassett, Daniel J. ; Young, Lisa R. ; Mavrodi, Dmitri ; Thomashow, Linda ; Lau, Gee. / Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. In: American Journal of Pathology. 2009 ; Vol. 175, No. 6. pp. 2473-2488.
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