TY - JOUR
T1 - Zika virus infects trabecular meshwork and causes trabeculitis and glaucomatous pathology in mouse eyes
AU - Singh, Pawan Kumar
AU - Kasetti, Ramesh B.
AU - Zode, Gulab S.
AU - Goyal, Anju
AU - Juzych, Mark S.
AU - Kumar, Ashok
N1 - Funding Information:
This study was supported by NIH grants R21AI135583, R01EY026964, and R01EY02738 (to A.K.) and Eversight Eye Bank grant (to P.K.S.). Our research is also supported in part by an unrestricted grant to the Kresge Eye Institute/Department of Ophthalmology, Visual, and Anatomical Sciences from Research to Prevent Blindness Inc. The immunology resource core is supported by an NIH center grant, P30EY004068. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2019 Singh et al.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including neurological (microcephaly) and ocular pathologies such as retinal lesions, optic nerve abnormalities, chorioretinal atrophy, and congenital glaucoma. Only clinical case reports have linked ZIKV infection to causing glaucoma, a major blinding eye disease. In the present study, we have investigated the role of ZIKV in glaucoma pathophysiology using in vitro and in vivo experimental models. We showed that human primary trabecular meshwork (Pr. TM) cells, as well as a human GTM3 cell line, were permissive to ZIKV infection. ZIKV induced the transcription of various genes expressing pattern recognition receptors (TLR2, TLR3, and RIG-I), cytokines/chemokines (TNF-α, IL-1β, CCL5, and CXCL10), interferons (IFN-α2, IFN-β1, and IFN-γ), and interferon-stimulated genes (ISG15 and OAS2) in Pr. TM cells. ZIKV infection in IFNAR1-/- and wild-type (WT) mouse eyes resulted in increased intraocular pressure (IOP) and the development of chorioretinal atrophy. Anterior chamber (AC) inoculation of ZIKV caused infectivity in iridocorneal angle and TM, leading to the death of TM cells in the mouse eyes. Moreover, anterior segment tissue of infected eyes exhibited increased expression of inflammatory mediators and interferons. Furthermore, ZIKV infection in IFNAR1-/- mice resulted in retinal ganglion cell (RGC) death and loss, coinciding with optic nerve infectivity and disruption of anterograde axonal transport. Because of similarity in glaucomatous pathologies in our study and other experimental glaucoma models, ZIKV infection can be used to study infectious triggers of glaucoma, currently an understudied area of investigation.
AB - Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including neurological (microcephaly) and ocular pathologies such as retinal lesions, optic nerve abnormalities, chorioretinal atrophy, and congenital glaucoma. Only clinical case reports have linked ZIKV infection to causing glaucoma, a major blinding eye disease. In the present study, we have investigated the role of ZIKV in glaucoma pathophysiology using in vitro and in vivo experimental models. We showed that human primary trabecular meshwork (Pr. TM) cells, as well as a human GTM3 cell line, were permissive to ZIKV infection. ZIKV induced the transcription of various genes expressing pattern recognition receptors (TLR2, TLR3, and RIG-I), cytokines/chemokines (TNF-α, IL-1β, CCL5, and CXCL10), interferons (IFN-α2, IFN-β1, and IFN-γ), and interferon-stimulated genes (ISG15 and OAS2) in Pr. TM cells. ZIKV infection in IFNAR1-/- and wild-type (WT) mouse eyes resulted in increased intraocular pressure (IOP) and the development of chorioretinal atrophy. Anterior chamber (AC) inoculation of ZIKV caused infectivity in iridocorneal angle and TM, leading to the death of TM cells in the mouse eyes. Moreover, anterior segment tissue of infected eyes exhibited increased expression of inflammatory mediators and interferons. Furthermore, ZIKV infection in IFNAR1-/- mice resulted in retinal ganglion cell (RGC) death and loss, coinciding with optic nerve infectivity and disruption of anterograde axonal transport. Because of similarity in glaucomatous pathologies in our study and other experimental glaucoma models, ZIKV infection can be used to study infectious triggers of glaucoma, currently an understudied area of investigation.
KW - Axonal transport
KW - Eye
KW - Glaucoma
KW - Intraocular pressure
KW - Ocular infection
KW - Optic nerve
KW - RGC
KW - Retina
KW - Trabeculitis
KW - Zika virus
UR - http://www.scopus.com/inward/record.url?scp=85065797845&partnerID=8YFLogxK
U2 - 10.1128/mSphere.00173-19
DO - 10.1128/mSphere.00173-19
M3 - Article
C2 - 31068433
AN - SCOPUS:85065797845
SN - 2379-5042
VL - 4
JO - mSphere
JF - mSphere
IS - 3
M1 - e00173-19
ER -