{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:01:45Z","timestamp":1773885705179,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013184","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000}}],"reference-count":106,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 EY021558"],"award-info":[{"award-number":["R01 EY021558"]}]},{"name":"NIH","award":["RO1 EY013124"],"award-info":[{"award-number":["RO1 EY013124"]}]},{"name":"NIH","award":["R00 EY031373"],"award-info":[{"award-number":["R00 EY031373"]}]},{"name":"NIH","award":["P20GM121176 -to the Autophagy, Inflammation and Metabolism Center at the University of New Mexico"],"award-info":[{"award-number":["P20GM121176 -to the Autophagy, Inflammation and Metabolism Center at the University of New Mexico"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>A highly contagious infection caused by human adenovirus species D (HAdV-D), epidemic keratoconjunctivitis (EKC) results in corneal subepithelial infiltration (SEI) by leukocytes, the hallmark of the infection. To date, the pathogenesis of corneal SEI formation in EKC is unresolved. HMGB1 (high-mobility group box 1 protein) is an alarmin expressed in response to infection and a marker of sepsis. Earlier studies using a different adenovirus species, HAdV-C, showed retention of HMGB1 in the infected cell nucleus by adenovirus protein VII, enabling immune evasion. Here, using HAdV-D we show cell-specific HMGB1 secretion by infected cells, and provide an HAdV-D specific mechanism for SEI formation in EKC. HMGB1 was secreted only upon infection of human corneal epithelial cells, not from other cell types, and only upon infection by HAdV-D types associated with EKC. Acetylated HMGB1 translocation from the nucleus to the cytoplasm, then to the extracellular milieu, was tightly controlled by CRM1 and LAMP1, respectively. Primary stromal cells when stimulated by rHMGB1 expressed proinflammatory chemokines. In a novel 3D culture system in tune with the architecture of the cornea, HMGB1 released by infected corneal epithelial cells induced leukocytic infiltrates either directly and\/or indirectly via stimulated stromal cells, which together explains SEI formation in EKC.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013184","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T14:20:07Z","timestamp":1747232407000},"page":"e1013184","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Virus and cell specific HMGB1 secretion and subepithelial infiltrate formation in adenovirus keratitis"],"prefix":"10.1371","volume":"21","author":[{"given":"Amrita","family":"Saha","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Mirazul","family":"Islam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashrafali Mohamed","family":"Ismail","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuel","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama R.","family":"Gullapali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Chodosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-5613","authenticated-orcid":true,"given":"Jaya","family":"Rajaiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"issue":"5","key":"ppat.1013184.ref001","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.cell.2020.08.021","article-title":"Emerging Pandemic Diseases: How We Got to COVID-19","volume":"182","author":"DM Morens","year":"2020","journal-title":"Cell"},{"issue":"23","key":"ppat.1013184.ref002","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1056\/NEJMoa2101544","article-title":"Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against 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