Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection
2003
No transgenic cystic fibrosis (CF) mouse model developed to date mimics the major clinical phenotype found in humans with CF, chronic Pseudomonas aeruginosa lung infection. In a transgenic CF transmembrane conductance regulator (cftr) mouse colony, we found WT, heterozygous, and homozygous CF mice housed in the same cage became chronically colonized in the oropharynx with environmental P. aeruginosa when the bacterium was present in drinking water. Elimination of P. aeruginosa from drinking water resulted in clearance in most WT and CF heterozygous, but not homozygous mice. For experimental evaluation, a combination of specific animal husbandry techniques and an oral infection route showed cftr−/− mice but not WT mice can be chronically colonized by P. aeruginosa with subsequent lung translocation, yielding a pathologic picture indicative of chronic lung infection. In some instances, mucoid isolates of P. aeruginosa were recovered from lungs, indicating conditions were present for conversion to mucoidy. Overexpression of human CFTR in the lungs of WT mice markedly accelerated the clearance rate of P. aeruginosa, demonstrating that lung levels of CFTR play an important role in defense against infection. P. aeruginosa mutants unable to express the surface polysaccharide alginate or the global regulator GacA were deficient in their ability to colonize the mice. CF mice made potent immune responses to P. aeruginosa outer membrane antigens. Overall, we found that under the proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluations of lung pathophysiology, bacterial virulence, and development of therapies aimed at treating CF lung disease.
1
Citations in 🌏 GeoScience
[
{
"id": "2379475",
"title": "Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia",
"abstract": "We developed a helper-dependent adenoviral vector for cystic fibrosis lung gene therapy. The vector expresses cystic fibrosis transmembrane conductance regulator (Cftr) using control elements from cytokeratin 18. The vector expressed properly localized CFTR in cultured cells and in the airway epithelia of mice. Cftr RNA and protein were present in whole lung and bronchioles, respectively, for 28 days after a vector dose. Acute inflammation was minimal to moderate. To test the therapeutic potential of the vector, we challenged mice with a clinical strain of Burkholderia cepacia complex (Bcc). Cftr knockout mice (but not Cftr+/+ littermates) challenged with Bcc developed severe lung histopathology and had high lung bacteria counts. Cftr knockout mice receiving gene therapy 7 days before Bcc challenge had less severe histopathology, and the number of lung bacteria was reduced to the level seen in Cftr+/+ littermates. These data suggest that gene therapy could benefit cystic fibrosis patients by reducing susceptibility to opportunistic pathogens.",
"source_url": "https://www.pnas.org/content/100/26/15364",
"doc_type": 4,
"year": 2003,
"issue": 26,
"volume": 100,
"first_page": 15364,
"last_page": 15369,
"citation_count": 0,
"reference_count": 7,
"venue": {
"id": 2110000201,
"name": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA",
"abbr": ""
},
"author": [
{
"id": 1002611339,
"name": "David R. Koehler"
},
{
"id": 1002611340,
"name": "Umadevi Sajjan"
},
{
"id": 1002118079,
"name": "Yu-Hua Chow"
},
{
"id": 1000550228,
"name": "Bernard Martin"
},
{
"id": 1002611341,
"name": "Geraldine Kent"
},
{
"id": 1002611342,
"name": "A. Keith Tanswell"
},
{
"id": 1001600853,
"name": "Colin McKerlie"
},
{
"id": 1002611343,
"name": "Janet F. Forstner"
},
{
"id": 1001720496,
"name": "Jim Hu"
}
],
"field": [
{
"id": 2007540617,
"name": "Pneumatocele"
},
{
"id": 2041068275,
"name": "Mucinous cystadenoma"
},
{
"id": 2022332494,
"name": "Air bronchogram"
},
{
"id": 2003602839,
"name": "Consolidation therapy"
}
],
"cite": [
{
"name": "GB/T 7714",
"text": "Koehler David R., Sajjan Umadevi, Chow Yu-Hua, et al. Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100(26): 15364-15369."
},
{
"name": "MLA",
"text": "Koehler, David R., et al. \"Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia\" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA., vol. 100, no. 26, 2003, pp. 15364-15369."
},
{
"name": "APA",
"text": "Koehler David R., Sajjan Umadevi, Chow Yu-Hua, Martin Bernard, Kent Geraldine, Tanswell A. Keith, ... & Hu Jim (2003). Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(26), 15364-15369."
},
{
"name": "BibTeX",
"text": "@inproceedings{Acemap2379475,\n title=\"Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia\",\n author=\"{David R. Koehler} and Umadevi {Sajjan} and {Yu-Hua Chow} and Bernard {Martin} and Geraldine {Kent} and {A. Keith Tanswell} and Colin {McKerlie} and {Janet F. Forstner} and Jim {Hu}\",\n journal=\"PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA\",\n volume=\"100\",\n number=\"26\",\n pages=\"15364--15369\",\n url=\"https://www.acemap.info/paper/2379475\",\n year=\"2003\"\n}"
}
]
}
]
