Diverse, variable ocular disease in a non-congenital murine model of Zika virus infection

Abstract

Purpose : Congenital and non-congenital ocular complications of Zika virus infection are becoming increasing recognized clinically. However, little is known regarding the ocular pathology of Zika virus infection. Here, we characterize the spectrum of ocular findings in a Zika virus susceptible
mouse model.

Methods : We took advantage of the fact that absent or blocked IFN-α/β provides a mouse animal model for evaluating the ocular pathology of Zika virus infection. Immunocompetent mice lacking the type I interferon receptor (IfnarI-/-) were given 1x10⁵ PFU of Zika virus through footpad
inoculation at 5 weeks of age and sacrificed at p2, p3, p5, p7, p9, p14, p21, p28. In other experiments we utilized Collaborative Cross mice controls resistant CC01 and susceptible CC071 strains treated with blocking monoclonal MAR1-5A3 specific for the INFAR-1 subunit of IFN-α/β receptor. Complete orbital exenterations were prepared in order to include the eye with its orbital structures and eyelids. Viremia was confirmed by PCR. Formalin fixed paraffin embedded sagittal sections through the optic nerve head were evaluated.

Results : All sham controls showed no evidence of inflammation or ocular disease. The earliest changes, which were detected 7 days after infection, consisted of a chronic inflammatory infiltrate of the vitreous sometimes involving the aqueous and angle. Involvement of the cornea ranged from bullous keratopathy to nonulcerative keratitis with stromal neovascularization. In one case, stromal necrosis with a hypopyon was observed. The eyelids were generally not involved. Bulbar conjunctivitis was present, and sometimes associated with marked orbital inflammatory disease with myositis. Inflammation of the lacrimal gland was observed, including necrosis in some cases. In cases with marked orbital inflammation, retinal necrosis was also often present. Otherwise, the retina was generally spared of pathology or inflammation.

Conclusions : Vitritis was the earliest finding appearing 7 days post-infection. Subsequent days showed involvement of the remaining ocular structures that was more widespread and variable than predicted. The findings included keratitis, conjunctivitis, dacryoadenititis, vitritis, anterior uveitis, orbital inflammation, and retinal necrosis. The murine model described here provides a useful system to study the pathophysiology of ocular ZIKV infection, and evaluate potential therapeutic approaches.

This is a 2020 ARVO Annual Meeting abstract.