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 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.

Pathobiology of Aspergillus Fumigatus Endophthalmitis in Immunocompetent and Immunocompromised Mice

“…TLRs have been shown to play a key role in the initiation of innate immune defense in the retina following bacterial and viral infection and TLR deficiency makes mice more susceptible to disease [26,27,28,40,44,45,46,47,48]. Several fungal ligands have been shown to interact with various TLRs, e.g., fungal chitin directly binds to TLR2 and induce an inflammatory response [49].…”

“…Immunostaining was performed on retinal cryosections following Aspergillus infection as described in our recent publications [27,28]. Briefly, infected and control mice eyes were enucleated and fixed in 4% PFA, dehydrated, and embedded in paraffin.…”

The Primary Cilium as a Therapeutic Target in Ocular Diseases

“…Therefore, the adjustment of intraocular pressure is particularly important for the treatment of glaucoma. As noted above, the primary cilia of the trabecular meshwork shorten in response to fluid flow and elevated aqueous humor pressure ( Singh et al., 2019 ). Lowe syndrome is an X-linked congenital disease that has glaucoma as one of its typical manifestations.…”

Zika virus-induced neuro-ocular pathology in immunocompetent mice correlates with anti-ganglioside autoantibodies

“…64 Our results are similar to those reported in C57BL/6 mice that developed retinal and corneal pathology, such as retinal edema and hyperplasia, following ZIKV infection. 56,65 Manangeeswaran et al found that retinal lesions and ocular pathology persists in C57BL/6 up to 90 days and correlates with elevated cytokine levels, but was performed in suckling neonatal mice. 66 Our data in the BALB/c model agree with the findings in C57BL/6 mice, and expand in the field of ZIKV neuro-ocular pathology and the underlying mechanisms, providing further insight into current knowledge gaps.…”