The Role of Caspase-12 in Retinal Bystander Cell Death and Innate Immune Responses against MCMV Retinitis.

Xinyan Zhang,Sylvia B Smith,Jinxian Xu,Ming Zhang,Zheng Dong,Brendan Marshall

doi:10.3390/ijms22158135

Abstract

(1) Background: caspase-12 is activated during cytomegalovirus retinitis, although its role is presently unclear. (2) Methods: caspase-12−/− (KO) or caspase-12+/+ (WT) mice were immunosup eyes were analyzed by plaque assay, TUNEL assay, immunohistochemical staining, western blotting, and real-time PCR. (3) Results: increased retinitis and a more extensive virus spread were detected in the retina of infected eyes of KO mice compared to WT mice at day 14 p.i. Compared to MCMV injected WT eyes, mRNA levels of interferons α, β and γ were significantly reduced in the neural retina of MCMV-infected KO eyes at day 14 p.i. Although similar numbers of MCMV infected cells, similar virus titers and similar numbers of TUNEL-staining cells were detected in injected eyes of both KO and WT mice at days 7 and 10 p.i., significantly lower amounts of cleaved caspase-3 and p53 protein were detected in infected eyes of KO mice at both time points. (4) Conclusions: caspase-12 contributes to caspase-3-dependent and independent retinal bystander cell death during MCMV retinitis and may also play an important role in innate immunity against virus infection of the retina.

Highlights

Human cytomegalovirus (HCMV) infects 50 to 80% of humans [1] and primary infection often persists throughout an individual’s lifetime
We report that caspase-12 plays an important role in restricting virus spread in the retina and limiting retinitis during ocular murine cytomegalovirus (MCMV) infection
As we have previously observed24, MCMV retinal infection was limited at day 14 p.i in wild type BALB/c mice, with fewer early antigen (EA) positive cells and less replicating virus compared to day 10 p.i

Summary

Introduction

Human cytomegalovirus (HCMV) infects 50 to 80% of humans [1] and primary infection often persists throughout an individual’s lifetime. Generally asymptomatic in immunocompetent hosts, HCMV infection presents a serious threat to immunosuppressed (IS) or immunonaive individuals [2]. HCMV retinitis is an opportunistic infection and the leading cause of vision impairment and blindness in HIV/AIDS patients without treatment, worldwide [3,4], less so than previously. The main causes of visual impairment during HCMV retinitis include macula or optic nerve disease, cataract, retinal detachment, macular edema, immune recovery uveitis, and epiretinal membrane [5,6], during which, necrotic damage to the fovea or optic nerve resulting from CMV infection plays a leading role [4]. Increasing evidence suggests that cell death of uninfected bystander retinal cells is an important component of the pathogenesis of cytomegalovirus retinitis and multiple regulated cell death pathways including apoptosis, necroptosis, pyroptosis, and AIF mediated apoptosis-like cell death may be involved in this process [11,14,21,22,23,24,25,26,27,28,29,30,31]

Methods

Results

Conclusion