Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Singh, Pawan Kumar; Singh, Sneha; Farr, Dustin; Kumar, Ashok

doi:10.1016/j.jtos.2019.03.006

Cited by 45 publications

(54 citation statements)

References 70 publications

(110 reference statements)

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“…To our knowledge, our study is the first, to show SARS-CoV-2 antigens in ocular tissue of COVID-19 patients that were procured without PVP-I disinfection treatment, supporting the idea that SARS-CoV-2 could infect corneal epithelial cells. We previously showed that corneal epithelia cells elicit innate responses upon viral stimuli such as ZIKV [ 30 ] or PolyI:C, a viral mimic of dsRNA [ 31 ]. However, further studies are necessary to understand if potential transmission of SARS-CoV-2 through the ocular surface is possible.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of SARS-CoV-2 in human post-mortem ocular tissues

Sawant¹,

et al. 2021

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Background SARS-CoV-2 is found in conjunctival swabs and tears of COVID-19 patients. However, the presence of SARS-CoV-2 has not been detected in the human eye to date. We undertook this study to analyze the prevalence of SARS-CoV-2 in human post-mortem ocular tissues. Methods The expression of SARS-CoV-2 RNA was assessed by RT-PCR in corneal and scleral tissues from 33 surgical-intended donors who were eliminated from a surgical use per Eye Bank Association of America (EBAA) donor screening guidelines or medical director review or positive COVID-19 test. Ocular levels of SARS-CoV-2 RNA (RT-PCR), Envelope and Spike proteins (immunohistochemistry) and anti -SARS-CoV-2 IgG and IgM antibodies (ELISA) in blood were evaluated in 10 COVID-19 donors. Findings Of 132 ocular tissues from 33 surgical-intended donors, the positivity rate for SARS-CoV-2 RNA was ∼13% (17/132). Of 10 COVID-19 donors, six had PCR positive post-mortem nasopharyngeal swabs whereas eight exhibited positive post-mortem anti -SARS-CoV-2 IgG levels. Among 20 eyes recovered from 10 COVID-19 donors: three conjunctival, one anterior corneal, five posterior corneal, and three vitreous swabs tested positive for SARS-CoV-2 RNA. SARS-CoV-2 spike and envelope proteins were detected in epithelial layer of the corneas that were procured without Povidone-Iodine (PVP–I) disinfection. Interpretations Our study showed a small but noteworthy prevalence of SARS-CoV-2 in ocular tissues from COVID-19 donors. These findings underscore the criticality of donor screening guidelines, post-mortem nasopharyngeal PCR testing and PVP-I disinfection protocol to eliminate any tissue harboring SARS-CoV-2 being used for corneal transplantation.

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Section: Discussionmentioning

confidence: 99%

Prevalence of SARS-CoV-2 in human post-mortem ocular tissues

Sawant¹,

et al. 2021

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“…Similarly, viral infections in humans, including those caused by HSV, herpes zoster virus (HZV), EBV, and CMV, have been shown to increase IOP (59–62). Whether the increased IOP observed in our study is due to general viral infection or is specific to ZIKV needs further investigation by challenging the mice with viruses closely related to ZIKV, e.g., dengue virus (25, 63), or unrelated viruses such as VZV. However, based on our in vitro and in vivo findings of susceptibility of TM cells to ZIKV and the induction of an inflammatory response, we propose that ZIKV-induced trabeculitis could be one of the potential mechanisms for increased IOP and glaucomatous pathology (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…All the cells (except C6/36, maintained at 28°C) were maintained at 37°C with 5% CO 2 . The plaque assay was performed using Vero cells as described in one of our recent studies (25).…”

Section: Methodsmentioning

confidence: 99%

“…Studies from our lab and others have shown that ZIKV infects a variety of retinal (6, 12, 17, 22–24), corneal (25), and other cell types, including neuronal cells (26, 27); placental cells (28, 29); skin fibroblasts, keratinocytes, and dendritic cells (30); and endometrial stromal cells (31). In vivo studies using local as well systemic infection in mouse models have demonstrated that ZIKV causes a variety of ocular pathologies and infects various parts of the eye including ciliary body, iris, conjunctiva, retina, and optic nerve head (6, 12, 17).…”

Section: Introductionmentioning

confidence: 94%

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

Singh

Kasetti

Zode

et al. 2019

mSphere

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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.

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“…One of the first properties attributed to ISG15 was that it could be secreted and act as cytokine (D'Cunha et al, 1996;Dos Santos and Mansur, 2017;Recht et al, 1991). Recently, exogenous free ISG15 has been shown to affect ZIKV replication in corneal cells (Singh et al, 2019). To explore whether extracellular ISG15 plays a role in controlling flavivirus replication in A549 cells, we pre-treated ISG15-deficient cells with 2 µg/ml of recombinant human ISG15 (rISG15) for 12 hours before DV infection.…”

Section: Extracellular Isg15 and Isgylation Deficiency Do Not Affect mentioning

confidence: 99%

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

Espada

Rocha

Santos

et al. 2019

Preprint

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The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system.Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the cells' immune response and restrict virus growth, suggesting that the IFNAR regulatory function of ISG15 is also antiviral. Our results suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host's IFN-I mediated response and promoting virus replication, adding another layer of complexity in the virus/host interaction interface.

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Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Cited by 45 publications

References 70 publications

Prevalence of SARS-CoV-2 in human post-mortem ocular tissues

Prevalence of SARS-CoV-2 in human post-mortem ocular tissues

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

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

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