Abstract
Zika virus (ZIKV), a mosquito-borne flavivirus, can cause severe eye disease and even blindness in newborns. However, ZIKV-induced retinal lesions have not been studied in a comprehensive way, mechanisms of ZIKV-induced retinal abnormalities are unknown, and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients. Here, we developed a novel mouse model of ZIKV infection to evaluate its impact on retinal structure. ZIKV (20 plaque-forming units) was inoculated into neonatal wild type C57BL/6J mice at postnatal day (P) 0 subcutaneously. Retinas of infected mice and age-matched controls were collected at various ages, and retinal structural alterations were analyzed. We found that ZIKV induced progressive neuronal and vascular damage and retinal inflammation starting from P8. ZIKV-infected retina exhibited dramatically decreased thickness with loss of neurons, initial neovascular tufts followed by vessel dilation and degeneration, increased microglia and leukocyte recruitment and activation, degeneration of astrocyte network and gliosis. The above changes may involve inflammation and endoplasmic reticulum stress-mediated cell apoptosis and necroptosis. Moreover, we evaluated the efficacy of preclinical drugs and the safety of ZIKV vaccine candidate in this mouse model. We found that ZIKV-induced retinal abnormalities could be blocked by a selective flavivirus inhibitor NITD008 and a live-attenuated ZIKV vaccine candidate could potentially induce retinal abnormalities. Overall, we established a novel mouse model and provide a direct causative link between ZIKV and retinal lesion in vivo, which warrants further investigation of the underlying mechanisms of ZIKV-induced retinopathy and the development of effective therapeutics.
Highlights
Zika virus (ZIKV) is an enveloped and spherical flavivirus which is transmitted by Aedes mosquitoes [15]
All retinal layers were intact and noted with dense ganglion cell layer (GCL), inner nuclear layer (INL) and outer nuclear layer (ONL), which were separated by two plexiform layers (inner plexiform layer (IPL) and outer plexiform layer (OPL)
We demonstrated that P0 pups inoculated with ZIKV developed significant loss of retinal ganglion cells (RGCs) and their axons, and retinal thinning during growing-up, which recapitulates a series of clinical features reflecting retinal neuronal and axonal degeneration when using non-invasive imaging to examine infants with Congenital Zika Syndrome, including neurosensory retinal thinning, discontinuation of the photoreceptor inner and outer segment junction, and optic nerve hypoplasia [33]
Summary
Zika virus (ZIKV) is an enveloped and spherical flavivirus which is transmitted by Aedes mosquitoes [15]. The virus was initially isolated from a rhesus monkey in the Zika Forest of Uganda in 1947 [8], and has caused outbreaks in Asia, the Pacific island and more recently in South and Central America [3, 4, 24], followed by a rapid spread to other countries during 2015–2016 including autochthonous transmissions in Florida and Texas in the United States [11]. In addition to neuronal damage in the brain, infants with congenital ZIKV infection are associated with a high rate of ocular abnormalities in which the most common lesions are retinal lesions, chorioretinal atrophy and optic nerve abnormalities. Mechanisms of ZIKV-induced retinal abnormalities are unknown and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients
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