{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T10:46:06Z","timestamp":1761129966194,"version":"3.37.3"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-20-COV1-00"],"award-info":[{"award-number":["ANR-20-COV1-00"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission through corneal graft is an ongoing debate and leads to strict restrictions in corneas procurement, leading to a major decrease in eye banking activity. The aims of this study are to specifically assess the capacity of human cornea to be infected by SARS-CoV-2 and promote its replication ex vivo, and to evaluate the real-life risk of corneal contamination by detecting SARS-CoV-2 RNA in corneas retrieved in donors diagnosed with Coronavirus Disease 2019 (COVID-19) and nonaffected donors.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>To assess the capacity of human cornea to be infected by SARS-CoV-2, the expression pattern of SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE-2) and activators TMPRSS2 and Cathepsins B and L in ocular surface tissues from nonaffected donors was explored by immunohistochemistry (<jats:italic>n =<\/jats:italic> 10 corneas, 78 \u00b1 11 years, 40% female) and qPCR (<jats:italic>n<\/jats:italic> = 5 corneas, 80 \u00b1 12 years, 40% female). Additionally, 5 freshly excised corneas (80 \u00b1 12 years, 40% female) were infected ex vivo with highly concentrated SARS-CoV-2 solution (10<jats:sup>6<\/jats:sup> median tissue culture infectious dose (TCID<jats:sub>50<\/jats:sub>)\/mL). Viral RNA was extracted from tissues and culture media and quantified by reverse transcription quantitative PCR (RT-qPCR) (viral RNA copies) 30 minutes (H0) and 24 hours (H24) after infection. To assess the risk of corneal contamination by SARS-CoV-2, viral RNA was tested by RT-qPCR (Ct value) in both corneas and organ culture media from 14 donors diagnosed with COVID-19 (74 \u00b1 10 years, 29% female) and 26 healthy donors (79 \u00b1 13 years, 57% female), and in organ culture media only from 133 consecutive nonaffected donors from 2 eye banks (73 \u00b1 13 years, 29% female).<\/jats:p>\n<jats:p>The expression of receptor and activators was variable among samples at both protein and mRNA level. Based on immunohistochemistry findings, ACE-2 was localized mainly in the most superficial epithelial cells of peripheral cornea, limbus, and conjunctiva, whereas TMPRSS2 was mostly expressed in all layers of bulbar conjunctiva.<\/jats:p>\n<jats:p>A significant increase in total and positive strands of IP4 RNA sequence (RdRp viral gene) was observed from 30 minutes to 24 hours postinfection in central cornea (1.1 \u00d7 10<jats:sup>8<\/jats:sup> [95% CI: 6.4 \u00d7 10<jats:sup>7<\/jats:sup> to 2.4 \u00d7 10<jats:sup>8<\/jats:sup>] to 3.0 \u00d7 10<jats:sup>9<\/jats:sup> [1.4 \u00d7 10<jats:sup>9<\/jats:sup> to 5.3 \u00d7 10<jats:sup>9<\/jats:sup>], <jats:italic>p<\/jats:italic> = 0.0039 and 2.2 \u00d7 10<jats:sup>7<\/jats:sup> [1.4 \u00d7 10<jats:sup>7<\/jats:sup> to 3.6 \u00d7 10<jats:sup>7<\/jats:sup>] to 5.1 \u00d7 10<jats:sup>7<\/jats:sup> [2.9 \u00d7 10<jats:sup>7<\/jats:sup> to 7.5 \u00d7 10<jats:sup>7<\/jats:sup>], <jats:italic>p<\/jats:italic> = 0.0117, respectively) and in corneoscleral rim (4.5 \u00d7 10<jats:sup>9<\/jats:sup> [2.7 \u00d7 10<jats:sup>9<\/jats:sup> to 9.6 \u00d7 10<jats:sup>9<\/jats:sup>] to 3.9 \u00d7 10<jats:sup>10<\/jats:sup> [2.6 \u00d7 10<jats:sup>10<\/jats:sup> to 4.4 \u00d7 10<jats:sup>10<\/jats:sup>], <jats:italic>p<\/jats:italic> = 0.0039 and 3.1 \u00d7 10<jats:sup>8<\/jats:sup> [1.2 \u00d7 10<jats:sup>8<\/jats:sup> to 5.3 \u00d7 10<jats:sup>8<\/jats:sup>] to 7.8 \u00d7 10<jats:sup>8<\/jats:sup> [3.9 \u00d7 10<jats:sup>8<\/jats:sup> to 9.9 \u00d7 10<jats:sup>8<\/jats:sup>], <jats:italic>p<\/jats:italic> = 0.0391, respectively). Viral RNA copies in ex vivo corneas were highly variable from one donor to another. Finally, viral RNA was detected in 3 out of 28 corneas (11%) from donors diagnosed with COVID-19. All samples from the 159 nonaffected donors were negative for SARS-CoV-2 RNA. The main limitation of this study relates to the limited sample size, due to limited access to donors diagnosed with COVID-19 and concomitant decrease in the procurement corneas from nonaffected donors.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>In this study, we observed the expression of SARS-CoV-2 receptors and activators at the human ocular surface and a variable increase in viral RNA copies 24 hours after experimental infection of freshly excised human corneas. We also found viral RNA only in a very limited percentage of donors with positive nasopharyngeal PCR. The low rate of positivity in donors diagnosed with COVID-19 calls into question the utility of donor selection algorithms.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>Agence de la Biom\u00e9decine, PFS-20-011 <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.agence-biomedecine.fr\/\" xlink:type=\"simple\">https:\/\/www.agence-biomedecine.fr\/<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1003922","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T18:25:27Z","timestamp":1646159127000},"page":"e1003922","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Exploration of the ocular surface infection by SARS-CoV-2 and implications for corneal donation: An ex vivo study"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-3423","authenticated-orcid":true,"given":"Corantin","family":"Maurin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5153-617X","authenticated-orcid":true,"given":"Zhiguo","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marielle","family":"Mentek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-1263","authenticated-orcid":true,"given":"Paul","family":"Verhoeven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvie","family":"Pillet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Bourlet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Rogues","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Loup","family":"Pugniet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thierry","family":"Peyragrosse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Barallon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantal","family":"Perrache","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5619-7864","authenticated-orcid":true,"given":"In\u00e8s","family":"Aouimeur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Acquart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Ninotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Baud\u2019huin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-8338","authenticated-orcid":true,"given":"Bertrand","family":"Vabres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvain","family":"Poinard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Gain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-2875","authenticated-orcid":true,"given":"Gilles","family":"Thuret","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,3,1]]},"reference":[{"issue":"11","key":"pmed.1003922.ref001","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1056\/NEJM197903153001105","article-title":"Human-to-human transmission of rabies virus by corneal transplant","volume":"300","author":"SA Houff","year":"1979","journal-title":"N Engl J Med"},{"issue":"2","key":"pmed.1003922.ref002","first-page":"132","article-title":"Clinical evidence for hepatitis B transmission resulting from corneal transplantation","volume":"16","author":"RH Hoft","year":"1997","journal-title":"Cornea"},{"issue":"2","key":"pmed.1003922.ref003","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1001\/jamaophthalmol.2015.4776","article-title":"Global Survey of Corneal Transplantation and Eye Banking","volume":"134","author":"P Gain","year":"2016","journal-title":"JAMA Ophthalmol"},{"key":"pmed.1003922.ref004","unstructured":"D\u00e9cret n\u00b0 2021\u201351 du 21 janvier 2021, JORF n\u00b00019 (January 22, 2021). 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