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Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes.

ABSTRACT: Zika virus (ZIKV) is an important pathogen that causes not only neurologic, but also ocular, abnormalities. Thus, it is imperative that models to study ZIKV pathogenesis in the eye are developed to identify potential targets for interventions. Here, we studied ZIKV interactions with human retinal cells and evaluated ZIKV's pathobiology in mouse eyes. We showed that cells lining the blood-retinal barrier (BRB), the retinal endothelium, and retinal pigment epithelium (RPE) were highly permissive and susceptible to ZIKV-induced cell death. Direct inoculation of ZIKV in eyes of adult C57BL/6 and IFN-stimulated gene 15 (ISG15) KO mice caused chorioretinal atrophy with RPE mottling, a common ocular manifestation of congenital ZIKV infection in humans. This response was associated with induced expression of multiple inflammatory and antiviral (IFNs) response genes in the infected mouse retina. Interestingly, ISG15 KO eyes exhibited severe chorioretinitis, which coincided with increased retinal cell death and higher ZIKV replication. Collectively, our study provides the first evidence to our knowledge that ZIKV causes retinal lesions and infects the cells lining the BRB and that ISG15 plays a role in retinal innate defense against ZIKV infection. Our mouse model can be used to study mechanisms underlying ZIKV-induced chorioretinitis and to gauge ocular antiviral therapies.

SUBMITTER: Singh PK

PROVIDER: S-EPMC5313066 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes.

Singh Pawan Kumar PK Guest John-Michael JM Kanwar Mamta M Boss Joseph J Gao Nan N Juzych Mark S MS Abrams Gary W GW Yu Fu-Shin FS Kumar Ashok A

JCI insight 20170223 4

Zika virus (ZIKV) is an important pathogen that causes not only neurologic, but also ocular, abnormalities. Thus, it is imperative that models to study ZIKV pathogenesis in the eye are developed to identify potential targets for interventions. Here, we studied ZIKV interactions with human retinal cells and evaluated ZIKV's pathobiology in mouse eyes. We showed that cells lining the blood-retinal barrier (BRB), the retinal endothelium, and retinal pigment epithelium (RPE) were highly permissive a ...[more]

PMID: 28239662

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Project description:To examine the hypotheses that in glaucomatous eyes with single-hemifield damage, retinal blood flow (RBF) is significantly reduced in the retinal hemisphere corresponding with the abnormal visual hemifield and that there are significant associations among reduced retinal sensitivity (RS) in the abnormal hemifield, RBF, and structural measurements in the corresponding hemisphere.Prospective, nonrandomized, case-control study.Thirty eyes of 30 patients with glaucoma with visual field loss confined to a single hemifield and 27 eyes of 27 controls.Normal and glaucomatous eyes underwent spectral-domain optical coherence tomography (SD-OCT) and standard automated perimetry. Doppler SD-OCT with a double-circle scanning pattern was used to measure RBF. The RBF was derived from the recorded Doppler frequency shift and the measured angle between the beam and the vessel. Total and hemispheric RBF, retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) values were calculated. The RS values were converted to 1/Lambert. Analysis of variance and regression analyses were performed.Total and hemispheric RS, RBF, RNFL, and GCC values.The total RBF (34.6±12.2 ?l/minute) and venous cross-sectional area (0.039 ± 0.009 mm(2)) were reduced (P<0.001) in those with glaucoma compared with controls (46.5 ± 10.6 ?l/minute; 0.052 ± 0.012 mm(2)). Mean RBF was reduced in the abnormal hemisphere compared with the opposite hemisphere (15.3 ± 5.4 vs. 19.3 ± 8.4 ?l/minute; P = 0.004). The RNFL and GCC were thinner in the corresponding abnormal hemisphere compared with the opposite hemisphere (87.0 ± 20.2 vs. 103.7 ± 20.6 ?m, P = 0.002; 77.6 ± 12.1 vs. 83.6 ± 10.1 ?m, P = 0.04). The RBF was correlated with RNFL (r = 0.41; P = 0.02) and GCC (r = 0.43; P = 0.02) but not the RS (r = 0.31; P = 0.09) in the abnormal hemisphere. The RBF (19.3 ± 8.4 ?l/minute), RNFL (103.7 ± 20.6 ?m), and GCC (83.6 ± 10.1 ?m) were reduced (P<0.05) in the hemisphere with apparently normal visual field in glaucomatous eyes compared with the mean hemispheric values of the normal eyes (23.2 ± 5.3 ?l/minute, 124.8 ± 9.6 ?m, and 96.1 ± 5.7 ?m, respectively).In glaucomatous eyes with single-hemifield damage, the RBF is significantly reduced in the hemisphere associated with the abnormal hemifield. Reduced RBF is associated with thinner RNFL and GCC in the corresponding abnormal hemisphere. Reduced RBF and RNFL and GCC loss also are observed in the perimetrically normal hemisphere of glaucomatous eyes.

Project description:PurposeLipofuscin contained in the retinal pigment epithelium (RPE) is the main source of fundus autofluorescence (FAF), the target of an imaging method useful for estimating the progression of geographic atrophy (GA) in clinical trials. To establish a cellular basis for hyperfluorescent GA border zones, histologic autofluorescence (HAF) was measured at defined stages of RPE pathologic progression.DesignExperimental study.Participants and controlsTen GA donor eyes (mean age ± standard deviation, 87.1 ± 4.0 years) and 3 age-matched control eyes (mean age ± standard deviation, 84.0 ± 7.2 years) without GA.MethodsThe 10-micrometer-thick sections were divided into zones of RPE morphologic features according to an 8-point scale. Any HAF excited by 488 nm light was imaged by laser confocal microscopy. The HAF intensity summed along vertical lines perpendicular to Bruch's membrane at 0.2-?m intervals served as a surrogate for FAF. Intensity profiles in 151 zones were normalized to grade 0 at a standard reference location in each eye. Cross-sectional area, mean, and sum autofluorescence for individual RPE cells were measured (cellular autofluorescence [CAF]).Main outcome measuresStatistically significant differences in intensity and localization of HAF and CAF at defined stages of RPE morphologic progression for GA and control eyes.ResultsThe RPE morphologic features were most abnormal (cell rounding, sloughing, and layering; grade 2) and HAF intensity profiles were highest and most variable immediately adjacent to atrophic areas. Peaks in HAF intensity frequently were associated with vertically superimposed cells. The HAF value that optimally separated reactive RPE was 0.66 standard deviations more than the mean for uninvolved RPE and was associated with a sensitivity of 75.8% and a specificity of 76.3%. When variable cell area was accounted for, neither mean nor sum CAF differed significantly among the RPE pathologic grades.ConclusionsAreas with advanced RPE alterations are most likely to exhibit clinically recognizable patterns of elevated FAF around GA, but may not predict cells about to die, because of vertically superimposed cells and cellular fragments. These data do not support a role for lipofuscin-related cell death and call into question the rationale of treatments targeting lipofuscin.

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Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes.

Publications

Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes.

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