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Infection and Immunity, August 2001, p. 5138-5150, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5138-5150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftrminus /minus Mice

Uma Sajjan,1 George Thanassoulis,2,3 Vera Cherapanov,2,3 Annie Lu,1 Carola Sjolin,1 Brent Steer,1 Yi Jun Wu,1 Ori D. Rotstein,4 Geraldine Kent,1 Colin McKerlie,5 Janet Forstner,1 and Gregory P. Downey1,2,3,*

Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8,1 Division of Respirology, Department of Medicine,2 and Department of Surgery,4 The University of Toronto, Toronto, Ontario M5S 1A8, Comparative Research, Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario M4N 3M5,5 and The Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario M5G 2C4,3 Canada

Received 5 February 2001/Returned for modification 14 March 2001/Accepted 2 May 2001

Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia cepacia (genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs of Cftr m1unc-/- (Cftr-/-) and congenic Cftr+/+ controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptible Cftr-/- mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from the Cftr-/- mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages from Cftr-/- mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF.

* Corresponding author. Mailing address: Clinical Sciences Division, Rm. 6264 Medical Sciences Building, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada M5S 1A8. Phone: (416) 978-8923. Fax: (416) 971-2112. E-mail: gregory.downey{at}utoronto.ca.

Infection and Immunity, August 2001, p. 5138-5150, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5138-5150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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