{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:27:50Z","timestamp":1788449270908,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012156","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000}}],"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/ NEI","award":["R01EY032495"],"award-info":[{"award-number":["R01EY032495"]}]},{"DOI":"10.13039\/100018719","name":"School of Medicine, University of Missouri","doi-asserted-by":"publisher","award":["Research Start-up Funds"],"award-info":[{"award-number":["Research Start-up Funds"]}],"id":[{"id":"10.13039\/100018719","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>SARS-CoV-2 has been shown to cause wide-ranging ocular abnormalities and vision impairment in COVID-19 patients. However, there is limited understanding of SARS-CoV-2 in ocular transmission, tropism, and associated pathologies. The presence of viral RNA in corneal\/conjunctival tissue and tears, along with the evidence of viral entry receptors on the ocular surface, has led to speculation that the eye may serve as a potential route of SARS-CoV-2 transmission. Here, we investigated the interaction of SARS-CoV-2 with cells lining the blood-retinal barrier (BRB) and the role of the eye in its transmission and tropism. The results from our study suggest that SARS-CoV-2 ocular exposure does not cause lung infection and moribund illness in K18-hACE2 mice despite the extended presence of viral remnants in various ocular tissues. In contrast, intranasal exposure not only resulted in SARS-CoV-2 spike (S) protein presence in different ocular tissues but also induces a hyperinflammatory immune response in the retina. Additionally, the long-term exposure to viral S-protein caused microaneurysm, retinal pigmented epithelium (RPE) mottling, retinal atrophy, and vein occlusion in mouse eyes. Notably, cells lining the BRB, the outer barrier, RPE, and the inner barrier, retinal vascular endothelium, were highly permissive to SARS-CoV-2 replication. Unexpectedly, primary human corneal epithelial cells were comparatively resistant to SARS-CoV-2 infection. The cells lining the BRB showed induced expression of viral entry receptors and increased susceptibility towards SARS-CoV-2-induced cell death. Furthermore, hyperglycemic conditions enhanced the viral entry receptor expression, infectivity, and susceptibility of SARS-CoV-2-induced cell death in the BRB cells, confirming the reported heightened pathological manifestations in comorbid populations. Collectively, our study provides the first evidence of SARS-CoV-2 ocular tropism via cells lining the BRB and that the virus can infect the retina via systemic permeation and induce retinal inflammation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012156","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T17:45:51Z","timestamp":1712771151000},"page":"e1012156","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["SARS-CoV-2 infects cells lining the blood-retinal barrier and induces a hyperinflammatory immune response in the retina via systemic exposure"],"prefix":"10.1371","volume":"20","author":[{"given":"Monu","family":"Monu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraz","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel M.","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Balendiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5517-1120","authenticated-orcid":true,"given":"Pawan Kumar","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"ppat.1012156.ref001","article-title":"WHO Coronavirus (COVID-19) Dashboard","author":"Organization WH","year":"2023"},{"issue":"3","key":"ppat.1012156.ref002","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s40135-021-00271-3","article-title":"Impact of SARS-CoV-2 on Ocular Surface Pathology and Treatment Practices: a Review.","volume":"9","author":"S Bal","year":"2021","journal-title":"Curr Ophthalmol 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Abdul-Salam State","year":"2022","journal-title":"Rom J Ophthalmol"},{"issue":"7","key":"ppat.1012156.ref007","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1007\/s00417-022-05953-7","article-title":"Retinal vascular occlusions in COVID-19 infection and vaccination: a literature review","volume":"261","author":"S Yeo","year":"2023","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"2","key":"ppat.1012156.ref008","doi-asserted-by":"crossref","first-page":"660","DOI":"10.4103\/ijo.IJO_1723_22","article-title":"SARS-CoV-2 virus-induced bilateral acute iris transillumination syndrome: The first case series in literature.","volume":"71","author":"OB Comba","year":"2023","journal-title":"Indian J Ophthalmol"},{"issue":"2","key":"ppat.1012156.ref009","doi-asserted-by":"crossref","first-page":"663","DOI":"10.4103\/ijo.IJO_1246_22","article-title":"Central retinal artery occlusion with cilioretinal artery sparing secondary to COVID-19: Additional ocular complication.","volume":"71","author":"MR de Oliveira","year":"2023","journal-title":"Indian J Ophthalmol"},{"key":"ppat.1012156.ref010","doi-asserted-by":"crossref","first-page":"25158414221149916","DOI":"10.1177\/25158414221149916","article-title":"Ocular manifestations of COVID-19 in pediatric patients.","volume":"15","author":"P Ichhpujani","year":"2023","journal-title":"Ther Adv Ophthalmol"},{"key":"ppat.1012156.ref011","doi-asserted-by":"crossref","first-page":"101876","DOI":"10.1016\/j.ajoc.2023.101876","article-title":"Panuveitis and optic neuropathy following SARS-COV-2 in the absence of multisystem inflammatory syndrome in a child","volume":"32","author":"P Land","year":"2023","journal-title":"Am J Ophthalmol Case Rep"},{"key":"ppat.1012156.ref012","doi-asserted-by":"crossref","first-page":"701295","DOI":"10.3389\/fimmu.2021.701295","article-title":"Case Report: A Re-Positive Case of SARS-CoV-2 Associated With Glaucoma.","volume":"12","author":"X Zhou","year":"2021","journal-title":"Front Immunol."},{"issue":"4","key":"ppat.1012156.ref013","doi-asserted-by":"crossref","DOI":"10.1177\/11206721221113201","article-title":"Acute angle-closure glaucoma concurrent with COVID 19 infection; case report.","volume":"33","author":"S Ozmen","year":"2023","journal-title":"Eur J Ophthalmol."},{"key":"ppat.1012156.ref014","first-page":"421","article-title":"Clinical Profile of COVID-19 Patients Presenting with Uveitis\u2014A Short Case Series.","volume":"14","author":"S Iriqat","year":"2021","journal-title":"Int Med Case Rep J."},{"key":"ppat.1012156.ref015","doi-asserted-by":"crossref","first-page":"100550","DOI":"10.1016\/j.eclinm.2020.100550","article-title":"Retinal findings in patients with COVID-19: Results from the SERPICO-19 study.","volume":"27","author":"A Invernizzi","year":"2020","journal-title":"EClinicalMedicine."},{"key":"ppat.1012156.ref016","doi-asserted-by":"crossref","first-page":"e0005723","DOI":"10.1128\/cmr.00057-23","article-title":"Viral infections and pathogenesis of glaucoma: a comprehensive review.","author":"F Ahmad","year":"2023","journal-title":"Clin Microbiol Rev"},{"issue":"1","key":"ppat.1012156.ref017","first-page":"103","article-title":"Ocular Manifestations of COVID-19: A Systematic Review and Meta-analysis.","volume":"16","author":"N Nasiri","year":"2021","journal-title":"J Ophthalmic Vis Res"},{"key":"ppat.1012156.ref018","doi-asserted-by":"crossref","unstructured":"Vashishtha VM, Kumar P. Preliminary clinical characteristics of Pediatric Covid-19 cases during the ongoing Omicron XBB.1.16 driven surge in a north Indian city. medRxiv. 2023:2023.04.18.23288715. doi: 10.1101\/2023.04.18.23288715","DOI":"10.1101\/2023.04.18.23288715"},{"issue":"4","key":"ppat.1012156.ref019","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.jtos.2020.06.007","article-title":"ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection.","volume":"18","author":"L Zhou","year":"2020","journal-title":"Ocul Surf."},{"key":"ppat.1012156.ref020","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jtos.2020.05.013","article-title":"Co-expression of SARS-CoV-2 entry genes in the superficial adult human conjunctival, limbal and corneal epithelium suggests an additional route of entry via the ocular surface.","volume":"19","author":"J Collin","year":"2021","journal-title":"Ocul 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response.","volume":"23","author":"S Singh","year":"2022","journal-title":"Ocul Surf."},{"key":"ppat.1012156.ref037","first-page":"3650574","article-title":"SARS-CoV-2 Infection of Ocular Cells from Human Adult Donor Eyes and hESC-Derived Eye Organoids.","author":"B Makovoz","year":"2020","journal-title":"SSRN."},{"issue":"7","key":"ppat.1012156.ref038","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.stem.2021.04.028","article-title":"SARS-CoV-2 infects human adult donor eyes and hESC-derived ocular epithelium","volume":"28","author":"AZ Eriksen","year":"2021","journal-title":"Cell Stem Cell"},{"issue":"1","key":"ppat.1012156.ref039","doi-asserted-by":"crossref","first-page":"7675","DOI":"10.1038\/s41467-022-35225-1","article-title":"Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation","volume":"13","author":"GU Jeong","year":"2022","journal-title":"Nat 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Pathog."},{"issue":"10","key":"ppat.1012156.ref049","doi-asserted-by":"crossref","DOI":"10.3390\/v10100530","article-title":"Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier.","volume":"10","author":"S Singh","year":"2018","journal-title":"Viruses."},{"issue":"3","key":"ppat.1012156.ref050","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1128\/CVI.00347-09","article-title":"Nasolacrimal duct closure modulates ocular mucosal and systemic CD4(+) T-cell responses induced following topical ocular or intranasal immunization.","volume":"17","author":"AA Chentoufi","year":"2010","journal-title":"Clin Vaccine Immunol"},{"issue":"4","key":"ppat.1012156.ref051","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S1542-0124(12)70164-7","article-title":"Topical\/mucosal delivery of sub-unit vaccines that stimulate the ocular mucosal immune system.","volume":"4","author":"AB Nesburn","year":"2006","journal-title":"Ocul 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J Virol"},{"issue":"1","key":"ppat.1012156.ref053","doi-asserted-by":"crossref","first-page":"e0343621","DOI":"10.1128\/mbio.03436-21","article-title":"Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection In Vitro, despite Eliciting a Prolonged Antiviral Response.","volume":"13","author":"AM Gamage","year":"2022","journal-title":"mBio."},{"issue":"1","key":"ppat.1012156.ref054","doi-asserted-by":"crossref","first-page":"7092","DOI":"10.1038\/s41467-021-27318-0","article-title":"Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2.","volume":"12","author":"CF Hatton","year":"2021","journal-title":"Nat Commun."},{"issue":"1","key":"ppat.1012156.ref055","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12985-022-01814-1","article-title":"COVID-19 infection: an overview on cytokine storm and related interventions","volume":"19","author":"S Montazersaheb","year":"2022","journal-title":"Virol 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Sci."},{"issue":"1","key":"ppat.1012156.ref060","doi-asserted-by":"crossref","first-page":"e1011077","DOI":"10.1371\/journal.ppat.1011077","article-title":"Ebola virus disrupts the inner blood-retinal barrier by induction of vascular endothelial growth factor in pericytes.","volume":"19","author":"J Gao","year":"2023","journal-title":"PLoS Pathog."},{"issue":"3","key":"ppat.1012156.ref061","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.tim.2020.12.007","article-title":"Dysregulation of Cell Signaling by SARS-CoV-2","volume":"29","author":"RK Suryawanshi","year":"2021","journal-title":"Trends Microbiol"},{"issue":"4","key":"ppat.1012156.ref062","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.devcel.2020.12.010","article-title":"ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation","volume":"56","author":"G Miao","year":"2021","journal-title":"Dev 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