Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes

ABSTRACT 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 infe...

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Autores principales:	Pawan Kumar Singh, Ramesh B. Kasetti, Gulab S. Zode, Anju Goyal, Mark S. Juzych, Ashok Kumar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	RGC Zika virus axonal transport eye glaucoma intraocular pressure Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d4138ecea38441f2abf6e27f4be314c1
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spelling	oai:doaj.org-article:d4138ecea38441f2abf6e27f4be314c12021-11-15T15:22:20ZZika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes10.1128/mSphere.00173-192379-5042https://doaj.org/article/d4138ecea38441f2abf6e27f4be314c12019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00173-19https://doaj.org/toc/2379-5042ABSTRACT 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. IMPORTANCE Ocular complications due to ZIKV infection remains a major public health concern because of their ability to cause visual impairment or blindness. Most of the previous studies have shown ZIKV-induced ocular pathology in the posterior segment (i.e., retina) of the eye. However, some recent clinical reports from affected countries highlighted the importance of ZIKV in affecting the anterior segment of the eye and causing congenital glaucoma. Because glaucoma is the second leading cause of blindness worldwide, it is imperative to study ZIKV infection in causing glaucoma to identify potential targets for therapeutic intervention. In this study, we discovered that ZIKV permissively infects human TM cells and evokes inflammatory responses causing trabeculitis. Using a mouse model, we demonstrated that ZIKV infection resulted in higher IOP, increased RGC loss, and optic nerve abnormalities, the classical hallmarks of glaucoma. Collectively, our study provides new insights into ocular ZIKV infection resulting in glaucomatous pathology.Pawan Kumar SinghRamesh B. KasettiGulab S. ZodeAnju GoyalMark S. JuzychAshok KumarAmerican Society for MicrobiologyarticleRGCZika virusaxonal transporteyeglaucomaintraocular pressureMicrobiologyQR1-502ENmSphere, Vol 4, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	RGC Zika virus axonal transport eye glaucoma intraocular pressure Microbiology QR1-502
spellingShingle	RGC Zika virus axonal transport eye glaucoma intraocular pressure Microbiology QR1-502 Pawan Kumar Singh Ramesh B. Kasetti Gulab S. Zode Anju Goyal Mark S. Juzych Ashok Kumar Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
description	ABSTRACT 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. IMPORTANCE Ocular complications due to ZIKV infection remains a major public health concern because of their ability to cause visual impairment or blindness. Most of the previous studies have shown ZIKV-induced ocular pathology in the posterior segment (i.e., retina) of the eye. However, some recent clinical reports from affected countries highlighted the importance of ZIKV in affecting the anterior segment of the eye and causing congenital glaucoma. Because glaucoma is the second leading cause of blindness worldwide, it is imperative to study ZIKV infection in causing glaucoma to identify potential targets for therapeutic intervention. In this study, we discovered that ZIKV permissively infects human TM cells and evokes inflammatory responses causing trabeculitis. Using a mouse model, we demonstrated that ZIKV infection resulted in higher IOP, increased RGC loss, and optic nerve abnormalities, the classical hallmarks of glaucoma. Collectively, our study provides new insights into ocular ZIKV infection resulting in glaucomatous pathology.
format	article
author	Pawan Kumar Singh Ramesh B. Kasetti Gulab S. Zode Anju Goyal Mark S. Juzych Ashok Kumar
author_facet	Pawan Kumar Singh Ramesh B. Kasetti Gulab S. Zode Anju Goyal Mark S. Juzych Ashok Kumar
author_sort	Pawan Kumar Singh
title	Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
title_short	Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
title_full	Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
title_fullStr	Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
title_full_unstemmed	Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes
title_sort	zika virus infects trabecular meshwork and causes trabeculitis and glaucomatous pathology in mouse eyes
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d4138ecea38441f2abf6e27f4be314c1
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Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes

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