The best defense is a good offense
The cornea is under constant threat of attack by microorganisms. The layer of cells that line the cornea, known as epithelial cells, are the first line of defense against these pathogens, but the underlying molecular mechanisms that allow them to repel microbes are unknown. Tam et al. found that epithelial cells in the corneaexpress small antimicrobial peptides, portions of human cytokeratin 6A that defend the eye against infection. In the frames above, combined two-photon-confocal imaging shows the presence of Pseudomonas aeruginosa (green) on the corneas of wildtype mice (left) and mice that are cytokeratin 6A-deficient (right). They also captured video of Pseudomonas aeruginosa in the cornea.
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Abstract
Epithelial cells express antimicrobial proteins in response to invading pathogens, although little is known regarding epithelial defense mechanisms during healthy conditions. Here we report that epithelial cytokeratins have innate defense properties because they constitutively produce cytoprotective antimicrobial peptides. Glycine-rich C-terminal fragments derived from human cytokeratin 6A were identified in bactericidal lysate fractions of human corneal epithelial cells. Structural analysis revealed that these keratin-derived antimicrobial peptides (KDAMPs) exhibited coil structures with low α-helical content. Synthetic analogs of these KDAMPS showed rapid bactericidal activity against multiple pathogens and protected epithelial cells against bacterial virulence mechanisms, while a scrambled peptide showed no bactericidal activity. However, the bactericidal activity of a specific KDAMP was somewhat reduced by glycine-alanine substitutions. KDAMP activity involved bacterial binding and permeabilization, but the activity was unaffected by peptide charge or physiological salt concentration. Knockdown of cytokeratin 6A markedly reduced the bactericidal activity of epithelial cell lysates in vitro and increased the susceptibility of murine corneas to bacterial adherence in vivo. These data suggest that epithelial cytokeratins function as endogenous antimicrobial peptides in the host defense against infection and that keratin-derived antimicrobials may serve as effective therapeutic agents.
Authors
Connie Tam, James J. Mun, David J. Evans, Suzanne M.J. Fleiszig
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)