PMID- 33608598 OWN - NLM STAT- MEDLINE DCOM- 20211207 LR - 20230129 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 Feb 19 TI - Herpes simplex virus-1 KOS-63 strain is virulent and causes titer-dependent corneal nerve damage and keratitis. PG - 4267 LID - 10.1038/s41598-021-83412-9 [doi] LID - 4267 AB - To investigate the acute clinical, immunological, and corneal nerve changes following corneal HSV-1 KOS-63 strain inoculation. 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 days 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 Cochet-Bonnet esthesiometer. Naive, 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 x) and neovascularization (2.6 x ; p < 0.05). At 7 dpi Hd infected mice showed more severe corneal opacity (2.23 vs. 0.87; p = 0.0003), neovascularization (6.00 vs. 0.75; p < 0.0001), and blepharitis (3.11 vs. 2.06; p = 0.001) compared to the Ld group. At 3 dpi epitheliopathy was significantly larger in the Hd group (23.59% vs. 3.44%; p = 0.001). 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 naive 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 (p < 0.05). Leukocyte density showed a gradual increase over time from 1 to 7 dpi in both KOS-63 and McKrae-infected corneas. Corneal flow cytometric analysis (3 dpi) demonstrated a higher percentage of Gr-1 + (71.6 vs. 26.3) and CD11b + (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 naive 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 mm/mm2; p = 0.004). Corneal sensation decreased accordingly at 5 and 7 dpi 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. FAU - Moein, Hamid-Reza AU - Moein HR AD - Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA. AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. FAU - Sendra, Victor G AU - Sendra VG AD - Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA. AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. FAU - Jamali, Arsia AU - Jamali A AD - Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA. AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. FAU - Kheirkhah, Ahmad AU - Kheirkhah A AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. FAU - Harris, Deshea L AU - Harris DL AD - Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA. AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. FAU - Hamrah, Pedram AU - Hamrah P AD - Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 02111, USA. Phamrah@tuftsmedicalcenter.org. AD - Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. Phamrah@tuftsmedicalcenter.org. AD - Cornea Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. Phamrah@tuftsmedicalcenter.org. LA - eng GR - R01 EY022695/EY/NEI NIH HHS/United States GR - R01 EY029602/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210219 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Biomarkers) SB - IM MH - Animals MH - Biomarkers MH - Cornea/innervation/pathology/virology MH - Corneal Opacity/etiology/pathology MH - Disease Models, Animal MH - Disease Susceptibility MH - Female MH - Herpesvirus 1, Human/pathogenicity/*physiology MH - Keratitis, Herpetic/complications/*pathology/*virology MH - Male MH - Mice MH - Phenotype MH - Severity of Illness Index MH - Trigeminal Ganglion/metabolism/pathology/virology MH - *Viral Load MH - Virulence PMC - PMC7895966 COIS- The authors declare no competing interests. EDAT- 2021/02/21 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/02/19 CRDT- 2021/02/20 05:33 PHST- 2020/04/26 00:00 [received] PHST- 2021/01/27 00:00 [accepted] PHST- 2021/02/20 05:33 [entrez] PHST- 2021/02/21 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/02/19 00:00 [pmc-release] AID - 10.1038/s41598-021-83412-9 [pii] AID - 83412 [pii] AID - 10.1038/s41598-021-83412-9 [doi] PST - epublish SO - Sci Rep. 2021 Feb 19;11(1):4267. doi: 10.1038/s41598-021-83412-9.