Bacterial pneumonia is a frequent and deadly complication in hospitalized patients. Pseudomonas aeruginosa (PA) is an aerobic gram-negative bacterium that is the second most common cause of pneumonia in hospitalized patients, with mortality ranging from 60-90% in mechanically ventilated with pneumonia due to PA pneumonia. Innate host responses to PA are initiated by selected toll like receptors (TLR), including TLR4, which recognizes LPS, and TLR5, which is activated by flagellin. Flagellin stimulates protective immunity against diverse microbial pathogens, including bacteria and viruses. We have recently found that flagellin is a major inducer of the cationic peptide cathelicidin related antimicrobial peptide (CRAMP). CRAMP exerts important bactericidal and immunomodulatory properties that may contribute to the protective effects of flagellin observed in both infectious and non-infectious models. The central hypothesis of this revised proposal is that Pseudomonas flagellin stimulates protective lung innate mucosal immunity, which is mediated, in part, by the induction of the cationic antimicrobial peptide CRAMP.
The Specific Aims of the proposal are as follows:
Specific Aim 1. Determine the role of the cationic antimicrobial peptide CRAMP in mucosal innate responses during PA pneumonia Specific Aim 2. Determine the mechanism of flagellin-induced stimulation of protective lung innate antibacterial immunity The studies proposed will provide important insights into the role of cathelicidins in lung antibacterial host defense, and may potentially identify novel approaches to stimulate lung mucosal immunity that can be used to prevent or treat pneumonia in hospitalized patients.

Public Health Relevance

Lung infection due to Pseudomonas aeruginosa continues to be a major cause of both morbidity and mortality in the United States. We have identified flagellin as a potent inducer of protective innate responses against this organism in experimental Pseudomonas pneumonia. Flagellin-induced protection is mediated, in part, by the antimicrobial peptide cathelicidin related antimicrobial peptide (CRAMP). The studies proposed in this application may identify novel means to prevent and possibly treat patients with respiratory tract infections due to P. aeruginosa.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097564-03
Application #
8212532
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (02))
Program Officer
Banks-Schlegel, Susan P
Project Start
2010-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$413,710
Indirect Cost
$126,201
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Yu, Fu-shin; Cornicelli, Matthew D; Kovach, Melissa A et al. (2010) Flagellin stimulates protective lung mucosal immunity: role of cathelicidin-related antimicrobial peptide. J Immunol 185:1142-9

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