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MyD88 Regulation of Fusarium Keratitis Is Dependent on TLR4 and IL-1R1 but Not TLR2¹

Ahmad B. Tarabishy^*, Bishr Aldabagh^*, Yan Sun^*, Yoshifumi Imamura, Pranab K. Mukherjee, Jonathan H. Lass^*, Mahmoud A. Ghannoum^, and Eric Pearlman^2,*

^* Department of Ophthalmology and Visual Sciences, Department of Dermatology, and Center for Medical Mycology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106

The fungal pathogens Fusarium solani and Fusarium oxysporum cause severe corneal disease in the United States and worldwide and were the causative organisms in a recent outbreak of contact lens-associated keratitis. To characterize innate immunity in Fusarium keratitis, we developed a murine model in which conidia are injected into the corneal stroma. Immunocompetent C57BL/6 mice rapidly developed severe corneal opacification associated with neutrophil infiltration and clearance of Fusarium hyphae. In contrast, neutrophil infiltration was delayed in MyD88^–/– mice, resulting in uncontrolled growth of Fusarium hyphae in the corneal stroma and anterior chamber, and eventually resulting in corneal perforation. Corneal opacification scores in TLR2^–/–, TLR4^–/–, and TLR2/4^–/– mice were similar to those of C57BL/6 mice; however, TLR4^–/– and TLR2/4^–/– mice had impaired antifungal responses. The phenotype of infected IL-1R1^–/– mice was similar to that of MyD88^–/– mice, with uncontrolled fungal growth resulting in corneal perforation. IL-1R1^–/– mice also produced significantly less CXCL1/KC in the corneal stroma compared with C57BL/6 mice consistent with delayed neutrophil recruitment to the corneal stroma. Together, these findings indicate that IL-1R1 and MyD88 regulate CXC chemokine production and neutrophil recruitment to the cornea, and that TLR4 has an important role in controlling growth and replication of these pathogenic fungi.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01EY018612 (to E.P.), P30-EY11373 (to E.P.), R01DE017486 (to M.A.G.), and R01DE13932 (to M.A.G.) and by a Research to Prevent Blindness Foundation Senior Investigator Award (to E.P.). We also acknowledge support from the National Institutes of Health (R01 AI035097-10) and Bristol-Myers Squibb Freedom to Discover Award (to M.A.G.), American Heart Association Scientist Development Grant 0335313N (to P.K.M.), and Research to Prevent Blindness and Ohio Lions Eye Research Foundation unrestricted awards (to J.H.L.).

² Address correspondence and reprint requests to Dr. Eric Pearlman, Department of Ophthalmology and Visual Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106. E-mail address: Eric.Pearlman{at}case.edu

³ Abbreviation used in this paper: ROS, reactive oxygen species.

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