MyD88 regulation of Fusarium keratitis is dependent on TLR4 and IL-1R1 but not TLR2.
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.
Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Ahmad B
AB
Tarabishy
Bishr
B
Aldabagh
Yan
Y
Sun
Yoshifumi
Y
Imamura
Pranab K
PK
Mukherjee
Jonathan H
JH
Lass
Mahmoud A
MA
Ghannoum
Eric
E
Pearlman
D000818:Animals; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D005670:Fusarium / Q000502:physiology*; D007167:Immunotherapy; D007634:Keratitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D054360:Chemokine CXCL1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4