@article {1580465,
	title = {Herpes simplex virus-1 KOS-63 strain is virulent and causes titer-dependent corneal nerve damage and keratitis},
	journal = {Sci Rep},
	volume = {11},
	number = {1},
	year = {2021},
	month = {2021 Feb 19},
	pages = {4267},
	abstract = {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\&nbsp;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\&nbsp;Cochet-Bonnet esthesiometer. Na{\"\i}ve, 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 {\texttimes}) and neovascularization (2.6 {\texttimes} ; p \&lt; 0.05). At 7\&nbsp;dpi Hd infected mice showed more severe corneal opacity (2.23 vs. 0.87; p = 0.0003), neovascularization (6.00 vs. 0.75; p \&lt; 0.0001), and blepharitis (3.11 vs. 2.06; p = 0.001) compared to the Ld group. At 3\&nbsp;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 na{\"\i}ve 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 \&lt; 0.05). Leukocyte density showed a gradual increase over time from 1 to 7\&nbsp;dpi in both KOS-63 and McKrae-infected corneas. Corneal flow cytometric analysis (3\&nbsp;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 na{\"\i}ve 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\&nbsp;mm/mm2; p = 0.004). Corneal sensation decreased accordingly at 5 and 7\&nbsp;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.},
	issn = {2045-2322},
	doi = {10.1038/s41598-021-83412-9},
	author = {Moein, Hamid-Reza and Sendra, Victor G and Jamali, Arsia and Kheirkhah, Ahmad and Harris, Deshea L and Hamrah, Pedram}
}
