TY - JOUR
T1 - Zika virus induces neuronal and vascular degeneration in developing mouse retina
AU - Li, Yi
AU - Shi, Shuizhen
AU - Xia, Fan
AU - Shan, Chao
AU - Ha, Yonju
AU - Zou, Jing
AU - Adam, Awadalkareem
AU - Zhang, Ming
AU - Wang, Tian
AU - Liu, Hua
AU - Shi, Pei Yong
AU - Zhang, Wenbo
N1 - Funding Information:
This work was supported in part by National Institutes of Health grant EY029112 (to. W.Z. and T.W.), EY022694 and EY026629, Retina Research Foundation, the Institute for Human Infections & Immunity, and UT System Faculty STARs Award (to W.Z.); and National Institutes of Health grant EY031054, Texas Alzheimer’s Research Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer’s Disease and Related Disorders 2020-63-92-JI, and the Sealy Center for Vector-borne and Zoonotic Diseases (to H.L.). P.-Y.S. was supported by NIH grants AI134907 and UL1TR001439, and awards from the Sealy & Smith Foundation, Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Gilson Longenbaugh Foundation, and the Summerfield Robert Foundation.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Drug efficacy
KW - Endoplasmic reticulum stress
KW - Inflammation
KW - Neuronal degeneration
KW - Retina
KW - Vaccine safety
KW - Vascular degeneration
KW - Zika virus
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U2 - 10.1186/s40478-021-01195-6
DO - 10.1186/s40478-021-01195-6
M3 - Article
C2 - 34034828
AN - SCOPUS:85106860321
SN - 2051-5960
VL - 9
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 97
ER -