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J Leukoc Biol. 2019 Jan 28. doi: 10.1002/JLB.4HI0918-364RR. [Epub ahead of print]

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections.

Author information

1
Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Proteomics and Signal Transduction Department, Max Planck Institute of Biochemistry, Martinsried, Germany.
3
MedImmune, LLC, Gaithersburg, Maryland, USA.
4
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
5
Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Pseudomonas aeruginosa-induced corneal keratitis is a sight-threatening disease. The rise of antibiotic resistance among P. aeruginosa keratitis isolates makes treatment of this disease challenging, emphasizing the need for alternative therapeutic modalities. By comparing the responses to P. aeruginosa infection between an outbred mouse strain (Swiss Webster, SW) and a susceptible mouse strain (C57BL6/N), we found that the inherent neutrophil-killing abilities of these strains correlated with their susceptibility to infection. Namely, SW-derived neutrophils were significantly more efficient at killing P. aeruginosa in vitro than C57BL6/N-derived neutrophils. To interrogate whether the distinct neutrophil killing capacities were dependent on endogenous or exogenous factors, neutrophil progenitor cell lines were generated. The in vitro differentiated neutrophils from either SW or C57BL6/N progenitors retained the differential killing abilities, illustrating that endogenous factors conferred resistance. Consistently, quantitative LC-MS/MS analysis revealed strain-specific and infection-induced alterations of neutrophil proteomes. Among the distinctly elevated proteins in the SW-derived proteomes were α-mannosidases, potentially associated with protection. Inhibition of α-mannosidases reduced neutrophil bactericidal functions in vitro. Conversely, topical application of α-mannosidases reduced bacterial biofilms and burden of infected corneas. Cumulatively, these data suggest novel therapeutic approaches to control bacterial biofilm assembly and improve bacterial clearance via enzymatic treatments.

KEYWORDS:

P. aeruginosa; biofilms; innate immunity; neutrophils

PMID:
30690787
DOI:
10.1002/JLB.4HI0918-364RR

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