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M. G. Gadjeva, T. Zaidi, G. Pier; Macrophage Migration Inhibitory Factor Promotes Pseudomonas Aruginosa-Induced Keratitis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3899.
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Pseudomonas aeruginosa causes severe sight-threatening corneal infections, with the inflammatory response to the pathogen being the major factor resulting in damage to the cornea that leads to loss of visual acuity.
In this study we examined the role of Macrophage Migration Inhibitory Factor (MIF) in regulation of the immune response to P. aeruginosa-induced keratitis.
Mice knocked-out for MIF and wild type control mice were infected with different strains of P. aeruginosa, and disease progression was examined by analyzing the bacterial burdens, the degree of neutrophil recruitment and inflammatory responses.
We found that mice deficient for MIF, a key regulator of inflammation, had significantly reduced consequences from P. aeruginosa-induced acute keratitis. This improvement in the outcome was manifested as improved bacterial clearance, decreased neutrophil infiltration, and decreased inflammatory responses when P. aeruginosa-infected MIF knock out (KO) mice were compared to infected wild type mice. Recombinant MIF applied to infected corneas restored the susceptibility of MIF deficient mice to P. aeruginosa-induced disease, demonstrating that MIF is necessary and sufficient to cause significant pathology at this immune privileged site. A MIF inhibitor administered during P. aeruginosa-induced infection ameliorated the disease-associated pathology. MIF regulated epithelial cell responses to infection by enhancing synthesis of proinflammatory mediators in response to P. aeruginosa infection and by promoting bacterial invasion of corneal epithelial cells, a correlate of virulence in the keratitis model.
Our results uncover a host factor that elevates inflammation and propagates bacterial cellular invasion, and further suggest that inhibition of MIF during infection may have a beneficial therapeutic effect.
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