Earlier reports of experimental fungal keratitis showed an important role of the host response in regulating disease, as immunosuppressed animals showed impaired cellular infiltration of the cornea and impaired fungal killing.
33–36 Our current findings using cyclophosphamide-immunosuppressed mice infected with
Fusarium grown as biofilm on contact lenses are consistent with those reports, as the cyclophosphamide-treated mice had significantly impaired capability of killing the fungus.
36 We extended these studies by identifying specific mediators of the host cell response. We found that the IL-1R1
−/− and MyD88
−/− mice had a phenotype similar to that of the cyclophosphamide-treated mice, with uncontrolled fungal growth, leading to corneal perforation. MyD88 is an adaptor molecule that is recruited early in the signaling pathway of IL-1R1 and which serves as a platform for recruitment of IRAK, IRAK4, and TRAF6. Phosphorylation of these kinases leads to NFκB formation and translocation into the nucleus and production of neutrophil chemotactic cytokines such as CXCL1.
37,38 MyD88 is also essential for TLR2 and TLR4 signaling, and although TLR2 and TLR4 have no apparent role in the development of corneal opacification, TLR4
−/− mice have an impaired ability to clear the infection, implicating this receptor in fungal killing as. We reported similar results in a model of trauma-induced
Fusarium keratitis in which conidia are injected directly into the corneal stroma.
17 In that study, the TLR4
−/− and TLR2/4
−/− mice had impaired fungal clearance, although the organisms were eventually cleared. Taken together with current findings, we suggest that TLR4 expression on neutrophils is important in recognition and killing of fungal hyphae.
27 These independent observations demonstrate that despite differences in fungal biofilm and resident corneal cell type that recognize conidia and hyphae (
Table 1), there are common mediators that regulate the host response to fungal pathogens. Similar results were detected in a model of
Aspergillus keratitis (Pearlman E, unpublished observations, 2009).