title: Topical flagellin protects the injured corneas from Pseudomonas aeruginosa infection.
abstract: Among bacterial pathogens, Pseudomonas (P.) aeruginosa infection is the most sight threatening. The corneal innate immune responses are key mediators of the host's defense to P. aeruginosa. Using a mouse model of Pseudomonas keratitis, we evaluated the protective effects of topical application of flagellin, a ligand for Toll-Like receptor 5 (TLR5), on the development of Pseudomonas keratitis and elucidated the underlying mechanisms. Topical application of purified flagellin 6 and 24 h prior to P. aeruginosa inoculation on injured mouse corneas significantly attenuated clinical symptoms of P. aeruginosa keratitis, decreased bacterial burden, and suppressed infection induced inflammation in the B6 mouse cornea. Topical application of flagellin on wounded cornea induced PMN infiltration and markedly upregulated cathelicidin-related antimicrobial peptide (CRAMP) expression. In PMN depleted mice, flagellin promoted bacterial clearance in the cornea compared to that of the PBS treated mice, but was unable to prevent corneal perforation and systemic bacterial dissemination and sepses. Deletion of CRAMP increased corneal susceptibility to P. aeruginosa and abolished flagellin-induced protection in B6 mice. Our findings illustrate the profound protective effect of flagellin on the cornea innate defense, a response that can be exploited for prophylactic purposes to prevent contact lens associated Pseudomonas keratitis.
authors.affiliation: Departments of Ophthalmology and Anatomy & Cell Biology, Kresge Eye Institute, Wayne State University School of Medicine, 4717 St. Antoine, Detroit, MI 48201, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Fu-Shin X
authors.initials: FS
authors.lastname: Yu
mesh_terms: D000287:Administration, Topical; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D058491:Bacterial Load; D054804:Cathelicidins / Q000096:biosynthesis / Q000276:immunology; D003315:Cornea / Q000382:microbiology*; D065306:Corneal Injuries; D003320:Corneal Ulcer / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005408:Flagellin / Q000008:administration & dosage* / Q000276:immunology; D015870:Gene Expression; D007634:Keratitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D011552:Pseudomonas Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000472:pathogenicity; D018805:Sepsis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D005408:Flagellin