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Derek J Royer, Daniel J Carr; Complement C3 and CD4 T cells coordinate corneal sensation loss in HSV-1 keratitis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6414.
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© ARVO (1962-2015); The Authors (2016-present)
Sensory nerve damage accompanies corneal inflammation and opacification in many ocular surface diseases, yet the pathomechanisms underlying sensation loss remain indeterminate. This study tested the hypothesis that the complement cascade contributes to corneal sensation loss following herpes simplex virus type 1 (HSV-1) infection.
Corneal nerve integrity and function were assessed by confocal microscopy and Cochet-Bonnet esthesiometry. Sensory nerve pathology was investigated by modeling corneal HSV-1 infection in wild-type C57BL/6 (WT), complement C3 deficient (C3-/-), T cell receptor-deficient (TCRα-/-) and TCR-transgenic (OT-II) mice. Cellular immune mechanisms were explored via flow cytometry and adoptive transfer of congenic T cells. Local complement factor synthesis was characterized by real time PCR. Pharmacologic complement C3 depletion was mediated by ocular cobra venom factor (CVF) treatment.
Corneal sensation was normal in all mice at baseline. HSV-1 infection provoked corneal sensation loss and denervation in WT but not C3-/- or TCRα-/- mice between days 5 to 8 post-infection (p<0.001). Sensation loss was independent of viral burden. However, corneal sensation loss was observed in HSV-infected TCRα-/- mice after reconstitution with CD3+ T cells from WT or C3-/- donors (p<0.001). Using the same model, transfer of CD4+ T cells from WT but not OT-II donors provoked sensation loss following HSV-1 infection in TCRα-/- recipients (p<0.001). Complement C3 was transcriptionally upregulated in the cornea following HSV-1 infection (p<0.01). Depletion of C3 by ocular CVF treatment preserved corneal sensation (p<0.001) and reduced CD4+ T cell infiltration (p<0.05) in HSV-infected WT mice relative to vehicle-treated groups. Statistical differences were calculated by ANOVA with Tukey/Bonferroni multiple comparison tests.
Our results show that local complement C3 activation contributes to corneal sensory nerve damage in HSV-1 keratitis. However, this pathology also required tissue-infiltrating, antigen-specific CD4+ T cells. Further investigation is needed to differentiate the responsible complement pathways and develop target-specific treatments. Nonetheless, these findings point to the complement cascade as a viable therapeutic target for inflammatory ocular surface diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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