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Corneas of C57BL\/6 mice were inoculated with either low dose (Ld) or high dose (Hd) HSV-1 KOS-63 or culture medium. Clinical evaluation was conducted up to 7\u00a0days post inoculation (dpi). Viral titers were assessed by standard plaque assay. Excised corneas were stained for CD45 and beta-III tubulin. Corneal flow cytometry was performed to assess changes in leukocyte subpopulations. Corneal sensation was measured using a\u00a0Cochet-Bonnet esthesiometer. Na\u00efve, sham-infected (post scarification), and McKrae-infected C57BL\/6 corneas served as two negative and positive controls, respectively. Compared to Ld infected mice, Hd HSV-1 KOS-63 demonstrated higher incidence of corneal opacity (1.5\u2009\u00d7) and neovascularization (2.6\u2009\u00d7\u2009; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). At 7\u00a0dpi Hd infected mice showed more severe corneal opacity (2.23 vs. 0.87; <jats:italic>p<\/jats:italic>\u2009=\u20090.0003), neovascularization (6.00 vs. 0.75; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), and blepharitis (3.11 vs. 2.06; <jats:italic>p<\/jats:italic>\u2009=\u20090.001) compared to the Ld group. At 3\u00a0dpi epitheliopathy was significantly larger in the Hd group (23.59% vs. 3.44%; <jats:italic>p<\/jats:italic>\u2009=\u20090.001). Similarly, corneal opacity was significantly higher in Hd McKrae-infected corneas as compared with Ld McKrae-infected corneas at 3 and 5 dpi. No significant corneal opacity, neovascularization, blepharitis, and epitheliopathy were observed in na\u00efve or sham-infected mice. Higher viral titers were detected in corneas (1 and 3 dpi) and trigeminal ganglia (TG) (3 and 5 dpi) in Hd versus Ld KOS-63 groups (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Leukocyte density showed a gradual increase over time from 1 to 7\u00a0dpi in both KOS-63 and McKrae-infected corneas. Corneal flow cytometric analysis (3\u00a0dpi) demonstrated a higher percentage of Gr-1\u2009+\u2009(71.6 vs. 26.3) and CD11b\u2009+\u2009(90.6 vs. 41.1) cells in Hd versus Ld KOS-63 groups. Corneal nerve density significantly decreased in both Hd KOS-63 and Hd McKrae infected corneas in comparison with na\u00efve and sham-infected corneas. At 3 dpi corneal nerve density was lower in the Hd versus Ld KOS-63 groups (16.79 vs. 57.41\u00a0mm\/mm2; <jats:italic>p<\/jats:italic>\u2009=\u20090.004). Corneal sensation decreased accordingly at 5 and 7\u00a0dpi in both Ld and Hd KOS-63-infected mice. Corneal inoculation with HSV-1 KOS-63 strain shows acute keratitis and nerve degeneration in a dose-dependent fashion, demonstrating virulence of this strain.<\/jats:p>","DOI":"10.1038\/s41598-021-83412-9","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T16:02:53Z","timestamp":1613836973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Herpes simplex virus-1 KOS-63 strain is virulent and causes titer-dependent corneal nerve damage and keratitis"],"prefix":"10.1038","volume":"11","author":[{"given":"Hamid-Reza","family":"Moein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor G.","family":"Sendra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsia","family":"Jamali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Kheirkhah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deshea L.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedram","family":"Hamrah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"83412_CR1","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.survophthal.2012.01.005","volume":"57","author":"AV Farooq","year":"2012","unstructured":"Farooq, A. 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