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Fushin X Yu, Chen Dong, Nan Gao; Ubiquitin-Like Protein ISG15 in Host Defense against Candida albicans Infection in a Mouse Model of Fungal Keratitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1880.
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© ARVO (1962-2015); The Authors (2016-present)
ISG15, a di-ubiquitin-like protein, is critical for controlling certain viral and bacterial infections. We sought to determine if ISG15 plays a role in corneal innate immunity against fungal infection.
Scarified corneas of adult B6 mice were pretreated with the TLR5 ligand flagellin and then inoculated with C. albicans. The expression of ISG15 and other genes involved in ISGylation was determined by realtime PCR and ISG15 expression and distribution in infected corneas was assessed by immunohistochemistry. ISGylation was examined by Western blotting. SiRNA knockdown was used to elucidate the function of ISG15 in controlling fungal keratitis, through characterization on digital photography and clinical scoring, fungal counting, ELISA cytokine determination, and PMN infiltration measurement.
C. albicans infection induced the expression of ISG15, ISGylation associated genes (UBE1L, UBCH8 and HERC5), and ISG15 conjugation in mouse cornea epithelial cells. flagellin pretreatment enhanced innate immunity against C. albicans and augmented ISG15 expression and ISGylation. ISG15 was most highly expressed in epithelial cells while infiltrated neutrophils were also ISG15 positive. ISG15 downregulation increased keratitis severity and dampened flagellin-induced protection in B6 mouse corneas.
These findings, for the first time, demonstrate that ISG15-mediated ISGylation plays a critical role in controlling fungal keratitis. Additional studies are needed to clarify the role of this molecule in corneal innate immunity and infectious keratitis.
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