Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr{-}/{-} Mice

doi:10.1128/IAI.69.8.5138-5150.2001

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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 Cftr^/ 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 thissusceptibility remains incompletely understood. To study thisproblem, we developed a model of chronic pneumonia by repeatedinstillation of a clinical isolate of Burkholderia cepacia (genomovarIII, ET12 strain), an opportunistic gram-negative bacterium, froma case of CF into the lungs of Cftr ^m1unc/ (Cftr^/) and congenic Cftr^+/+ controls. Nine days after the last instillation, the CF transmembraneregulator knockout mice showed persistence of viable bacteriawith chronic severe bronchopneumonia while wild-type mice remainedhealthy. The histopathological changes in the lungs of the susceptibleCftr^/ mice were characterized by infiltration of a mixed inflammatory-cellpopulation into the peribronchiolar and perivascular spaces, Claracell hyperplasia, mucus hypersecretion in airways, and exudationinto alveolar airspaces by a mixed population of macrophages andneutrophils. An increased proportion of neutrophils was observedin bronchoalveolar lavage fluid from the Cftr^/ mice, which, despite an increased bacterial load, demonstratedminimal evidence of activation. Alveolar macrophages from Cftr^/ mice also demonstrated suboptimal activation. These observationssuggest that the pulmonary host defenses are compromised in lungsfrom animals with CF, as manifested by increased susceptibilityto bacterial infection and lung injury. This murine model of chronicpneumonia thus reflects, in part, the situation in human patientsand may help elucidate the mechanisms leading to defective hostdefense inCF.

^* 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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Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr/ Mice

Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr^/ Mice