Cornea

Gupta PK, Venkateswaran N. The role of KPI-121 0.25% in the treatment of dry eye disease: penetrating the mucus barrier to treat periodic flares. Ther Adv Ophthalmol 2021;13:25158414211012797.Abstract
The tear film, which includes mucins that adhere to foreign particles, rapidly clears allergens and pathogens from the ocular surface, protecting the underlying tissues. However, the tear film's ability to efficiently remove foreign particles during blinking can also pose challenges for topical drug delivery, as traditional eye drops (solutions and suspensions) are cleared from the ocular surface before the drug can penetrate into the conjunctival and corneal epithelium. In the past 15 years, there has been an increase in the development of nanoparticles with specialized coatings that have reduced affinity to mucins and are small enough in size to pass through the mucus barrier. These mucus-penetrating particles (MPPs) have been shown to efficiently penetrate the mucus barrier and reach the ocular surface tissues. Dry eye disease (DED) is a common inflammatory ocular surface disorder that often presents with periodic flares (exacerbations). However, currently approved immunomodulatory treatments for DED are intended for long-term use. Thus, there is a need for effective short-term treatments that can address intermittent flares of DED. Loteprednol etabonate, an ocular corticosteroid, was engineered to break down rapidly after administration to the ocular surface tissues and thereby reduce risks associated with other topical steroids. KPI-121 is an ophthalmic suspension that uses the MPP technology to deliver loteprednol etabonate more efficiently to the ocular tissues, achieving in animal models a 3.6-fold greater penetration of loteprednol etabonate to the cornea than traditional loteprednol etabonate ophthalmic suspensions. In clinical trials, short-term treatment with KPI-121 0.25% significantly reduced signs and symptoms of DED compared with its vehicle (placebo). Recently approved KPI-121 0.25%, with its novel drug delivery design and ease of use, has the potential to effectively treat periodic flares of DED experienced by many patients.
Yin J. Advances in corneal graft rejection. Curr Opin Ophthalmol 2021;32(4):331-337.Abstract
PURPOSE OF REVIEW: Immune rejection after corneal transplantation is a major risk for graft failure. We aim to summarize recent advances in the understanding and management of graft rejection. RECENT FINDINGS: Immune rejection remains the leading cause of graft failure in penetrating keratoplasty (PKP). While ABO blood type and sex match between donor and recipient may reduce rejection, human leucocyte antigens class II matching in a randomized study did not reduce the risk of rejection in high-risk PKP. Compared with PKP, deep anterior lamellar keratoplasty, descemet stripping automated endothelial keratoplasty, and descemet membrane endothelial keratoplasty have lower immune rejection rates of 1.7-13%, 5-11.4%, and 1.7-2.8%, respectively, based on long-term (5 years and more) studies. Whether immune rejection is a major risk factor for graft failure in these lamellar keratoplasties is unclear. While there have not been major advances in the systemic management of graft rejection, topical nonsteroid agents such as tacrolimus and anti-vascular endothelial growth factor have shown promise in high-risk cases. SUMMARY: Immune rejection remains the leading cause of graft failure in PKP. Lamellar keratoplasties have significantly lower rejection rates compared with PKP. The significance of rejection in the failure of lamellar grafts warrants further investigation.
Rubinfeld RS, Gum GG, Talamo JH, Parsons EC. The Effect of Sodium Iodide on Stromal Loading, Distribution and Degradation of Riboflavin in a Rabbit Model of Transepithelial Corneal Crosslinking. Clin Ophthalmol 2021;15:1985-1994.Abstract
Purpose: To evaluate effects of sodium iodide (NaI) on riboflavin concentration in corneal stroma before and during ultraviolet A (UVA) light exposure using a novel transepithelial corneal collagen crosslinking (CXL) procedure (EpiSmart CXL system, CXL Ophthalmics, Encinitas CA). Methods: Riboflavin solutions with NaI (Ribostat, CXL Ophthalmics, Encinitas CA) and without NaI were used for CXL in rabbits using EpiSmart. A pilot study determined sufficient riboflavin loading time. Four rabbits were dosed and monitored. Riboflavin fluorescence intensity was assessed from masked slit-lamp photos. A 12 min loading time was selected. Sixteen additional rabbits received the two formulae in contralateral eyes for CXL. Riboflavin uptake was assessed at 0, 10, 15, 20, 25, and 30 min of UVA exposure using a scale for riboflavin fluorescence previously validated against stromal concentration. Post sacrifice, corneal stromal samples were analyzed for concentrations of riboflavin and riboflavin 5'-phosphate. Results: Eyes dosed with NaI riboflavin had higher riboflavin grades compared to eyes dosed with the NaI-free riboflavin formulation immediately after riboflavin loading and persisting throughout UVA exposure, with significantly higher (P < 0.01 to < 0.05) riboflavin grades from 15 through 25 min of UVA exposure. Riboflavin grades decreased more slowly in eyes dosed with NaI riboflavin through 25 minutes of UVA exposure. Minor conjunctival irritation was noted with or without NaI. Conclusion: The addition of NaI to riboflavin solution is associated with increased riboflavin concentration in corneal stroma throughout a clinically relevant time course of UVA exposure. This effect may be a combination of enhanced epithelial penetration and reduced riboflavin photodegradation and should enhance intrastromal crosslinking.
Tahvildari M, Singh RB, Saeed HN. Application of Artificial Intelligence in the Diagnosis and Management of Corneal Diseases. Semin Ophthalmol 2021;36(8):641-648.Abstract
Diagnosis and treatment planning in ophthalmology heavily depend on clinical examination and advanced imaging modalities, which can be time-consuming and carry the risk of human error. Artificial intelligence (AI) and deep learning (DL) are being used in different fields of ophthalmology and in particular, when running diagnostics and predicting outcomes of anterior segment surgeries. This review will evaluate the recent developments in AI for diagnostics, surgical interventions, and prognosis of corneal diseases. It also provides a brief overview of the newer AI dependent modalities in corneal diseases.
Shanbhag SS, Shih G, Bispo PJM, Chodosh J, Jacobs DS, Saeed HN. Diphtheroids as Corneal Pathogens in Chronic Ocular Surface Disease in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. Cornea 2021;40(6):774-779.Abstract
PURPOSE: To characterize diphtheroid corneal infections in eyes in the chronic phase of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: Observational case series. RESULTS: Four eyes of 3 patients were included in this review. Each eye presented with persistent corneal epithelial defect with corneal thinning in the chronic phase of SJS/TEN. None of the epithelial defects were associated with stromal infiltration. The corneas were cultured at the time of workup of persistent epithelial defect (3 eyes) or at time of tectonic penetrating keratoplasty after perforation (1 eye). Cultures yielded abundant growth of Corynebacterium spp., including Corynebacterium jeikeium (n = 2), Corynebacterium glucuronolyticum (n = 1), and a multidrug-resistant Corynebacterium striatum isolate (n = 1). The ocular surface was stabilized with surgical intervention (1 eye) or with introduction of fortified topical antibiotic based on laboratory identification and susceptibility testing of the isolated organisms (3 eyes). Numerous risk factors for microbial keratitis were present in all 4 eyes. CONCLUSIONS: In eyes with a persistent corneal epithelial defect in the chronic phase of SJS/TEN, even in the absence of an infiltrate, corneal culture should be undertaken. Recognition and treatment of Corynebacterium spp. as opportunistic pathogens may lead to favorable outcomes in cases of clinically sterile ulceration during the chronic phase of SJS/TEN.
Norrick A, Esterlechner J, Niebergall-Roth E, Dehio U, Sadeghi S, Schröder HM, Ballikaya S, Stemler N, Ganss C, Dieter K, Dachtler A-K, Merz P, Sel S, Chodosh J, Cursiefen C, Frank NY, Auffarth GU, Ksander B, Frank MH, Kluth MA. Process development and safety evaluation of ABCB5 limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res Ther 2021;12(1):194.Abstract
BACKGROUND: While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5 LSCs derived from human cadaveric limbal tissue. METHODS: We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5 LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cells' engraftment potential, biodistribution behavior, and safety. RESULTS: ABCB5 LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. CONCLUSION: Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5 LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patient's LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea.
Islam R, Islam MM, Nilsson PH, Mohlin C, Hagen KT, Paschalis EI, Woods RL, Bhowmick SC, Dohlman CH, Espevik T, Chodosh J, Gonzalez-Andrades M, Mollnes TE. Combined blockade of complement C5 and TLR co-receptor CD14 synergistically inhibits pig-to-human corneal xenograft induced innate inflammatory responses. Acta Biomater 2021;127:169-179.Abstract
Inadequate supplies of donor corneas have evoked an escalating interest in corneal xenotransplantation. However, innate immune responses contribute significantly to the mechanism of xenograft rejection. We hypothesized that complement component C5 and TLR co-receptor CD14 inhibition would inhibit porcine cornea induced innate immune responses. Therefore, we measured cytokine release in human blood, induced by three forms of corneal xenografts with or without inhibitors. Native porcine cornea (NPC) induced interleukins (IL-1β, IL-2, IL-6, IL-8, IL-1ra), chemokines (MCP-1, MIP-1α, MIP-1β) and other cytokines (TNF, G-CSF, INF-γ, FGF-basic). Decellularized (DPC) and gamma-irradiated cornea (g-DPC) elevated the release of those cytokines. C5-blockade by eculizumab inhibited all the cytokines except G-CSF when induced by NPC. However, C5-blockade failed to reduce DPC and g-DPC induced cytokines. Blockade of CD14 inhibited DPC-induced cytokines except for IL-8, MCP-1, MIP-1α, and G-CSF, while it inhibited all of them when induced by g-DPC. Combined blockade of C5 and CD14 inhibited the maximum number of cytokines regardless of the xenograft type. Finally, by using the TLR4 specific inhibitor Eritoran, we showed that TLR4 activation was the basis for the CD14 effect. Thus, blockade of C5, when combined with TLR4 inhibition, may have therapeutic potential in pig-to-human corneal xenotransplantation. STATEMENT OF SIGNIFICANCE: Bio-engineered corneal xenografts are on the verge of becoming a viable alternative to allogenic human-donor-cornea, but the host's innate immune response is still a critical barrier for graft acceptance. By overruling this barrier, limited graft availability would no longer be an issue for treating corneal diseases. We showed that the xenograft induced inflammation is initiated by the complement system and toll-like receptor activation. Intriguingly, the inflammatory response was efficiently blocked by simultaneously targeting bottleneck molecules in the complement system (C5) and the TLR co-receptor CD14 with pharmaceutical inhibitors. We postulate that a combination of C5 and CD14 inhibition could have a great therapeutic potential to overcome the immunologic barrier in pig-to-human corneal xenotransplantation.
Böhm MS, Wylegala A, Leon P, Ong Tone S, Ciolino JB, Jurkunas UV. One-Year Clinical Outcomes of Preloaded Descemet Membrane Endothelial Keratoplasty Versus Non-Preloaded Descemet Membrane Endothelial Keratoplasty. Cornea 2021;40(3):311-319.Abstract
PURPOSE: To compare the one-year outcomes of preloaded Descemet membrane endothelial keratoplasty (pDMEK) and non-preloaded DMEK (n-pDMEK) in patients with Fuchs endothelial corneal dystrophy (FECD). METHODS: This retrospective comparative cohort study consecutively included 68 eyes with Fuchs endothelial corneal dystrophy who underwent either pDMEK (n = 38) or n-pDMEK (n = 30) performed by cornea fellows with an experienced surgeon between 2016 and 2018 at the Massachusetts Eye and Ear Infirmary. Exclusion criteria were previous surgery (other than uncomplicated cataract surgery) and any documented evidence of macular or other corneal diseases. Corrected distance visual acuity (CDVA), central corneal thickness, intraocular pressure, patient characteristics, postprocessing endothelial cell count, donor graft data, and complications were compared. RESULTS: CDVA showed similar results for pDMEK (0.12 ± 0.11 logarithm of the minimal angle of resolution [LogMAR]) and n-pDMEK (0.13 ± 0.13 LogMAR) (P = 0.827). Sixty-six percent of the pDMEK eyes and 57% of the n-pDMEK eyes achieved a VA of ≥0.1 LogMAR, and 95% and 97%, respectively, achieved a CDVA ≥0.3 LogMAR. The preoperative central corneal thickness of pDMEK and n-pDMEK (644 ± 62.2 μm, 660.5 ± 56.2 μm) decreased significantly after surgery (525.1 ± 43.6 μm, 526.5 ± 45.2 μm, P < 0.001), with no difference between groups (P = 0.840). The postprocessing endothelial cell count did not differ between pDMEK (2959.2 ± 182.9 cells/mm2) and n-pDMEK (2939.3 ± 278.7 cells/mm2) (P = 0.484). Complication rates were comparable with just the rebubbling performed in a minor procedure room showing a lower rate for pDMEK (13.16%) compared with n-pDMEK (33.33%) (P < 0.045). CONCLUSIONS: One-year clinical outcomes were similar between pDMEK and n-pDMEK procedures, rendering eye bank-prepared pDMEK tissues a useful tool in the treatment of endothelial dysfunction.
Sharifi S, Sharifi H, Guild C, Islam MM, Tran KD, Patzer C, Dohlman CH, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Toward electron-beam sterilization of a pre-assembled Boston keratoprosthesis. Ocul Surf 2021;20:176-184.Abstract
PURPOSE: To evaluate the effects of electron-beam (E-beam) irradiation on the human cornea and the potential for E-beam sterilization of Boston keratoprosthesis (BK) devices when pre-assembled with a donor cornea prior to sterilization. METHODS: Human donor corneas and corneas pre-assembled in BK devices were immersed in recombinant human serum albumin (rHSA) media and E-beam irradiated at 25 kGy. Mechanical (tensile strength and modulus, and compression modulus), chemical, optical, structural, and degradation properties of the corneal tissue after irradiation and after 6 months of preservation were evaluated. RESULTS: The mechanical evaluation showed that E-beam irradiation enhanced the tensile and compression moduli of human donor corneas, with no impact on their tensile strength. By chemical and mechanical analysis, E-beam irradiation caused a minor degree of crosslinking between collagen fibrils. No ultrastructural changes due to E-beam irradiation were observed. E-beam irradiation slightly increased the stability of the cornea against collagenase-induced degradation and had no impact on glucose diffusion. The optical evaluation showed transparency of the cornea was maintained. E-beam irradiated corneal tissues and BK-cornea pre-assembled devices were stable for 6 months after room-temperature preservation. CONCLUSIONS: E-beam irradiation generated no detrimental effects on the corneal tissues or BK-cornea pre-assembled devices and improved native properties of the corneal tissue, enabling prolonged preservation at room temperature. The pre-assembly of BK in a donor cornea, followed by E-beam irradiation, offers the potential for an off-the-shelf, ready to implant keratoprosthesis device.
Hossain P, Siffel C, Joseph C, Meunier J, Markowitz JT, Dana R. Patient-reported burden of dry eye disease in the UK: a cross-sectional web-based survey. BMJ Open 2021;11(3):e039209.Abstract
OBJECTIVES: To compare sociodemographics and vision-related quality of life (QoL) of individuals with or without dry eye disease (DED); and to explore the impact of DED symptom severity on visual function, activity limitations and work productivity. DESIGN: Cross-sectional web-based survey. SETTING: General UK population. PARTICIPANTS: Adults ≥18 years with (N=1002) or without (N=1003) self-reported DED recruited through email and screened. MAIN OUTCOME MEASURES: All participants completed the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25), with six additional questions (items A3-A8), and the EuroQol 5 dimensions 5 levels. DED participants also completed Impact of Dry Eye on Everyday Life questionnaire, 5-item Dry Eye Questionnaire and the Standardised Patient Evaluation of Eye Dryness questionnaire along with the Ocular Comfort Index, Work Productivity and Activity Impairment and the Eye Dryness Score (EDS), a Visual Analogue Scale. RESULTS: Baseline demographic and clinical characteristics were similar in participants with versus without DED (mean age, 55.2 vs 55.0 years; 61.8% vs 61.0% women, respectively) based on recruitment targets. Scores were derived from NEI VFQ-25 using the new 28-item revised VFQ (VFQ-28R) scoring. Mean (SD) VFQ-28R scores were lower in participants with versus without DED, indicating worse functioning (activity limitations, 73.3 (12.3) vs 84.4 (12.3); socioemotional functioning, 75.3 (21.5) vs 90.3 (16.2); total score, 71.6 (12.8) vs 83.6 (12.6)). Higher percentages of problems/inability to do activities were observed among those with versus without DED. The impact of DED on visual function was worse for participants with more severe DED symptoms, as assessed by EDS. In addition, a higher EDS was associated with worse symptoms on common DED scales and a worse impact on work productivity. CONCLUSIONS: DED symptoms were associated with negative effects on visual function, activities and work productivity, whereas worse DED symptoms had a greater impact on vision-related QoL and work productivity.
Martinez-Carrasco R, Argüeso P, Fini EM. Membrane-associated mucins of the human ocular surface in health and disease. Ocul Surf 2021;21:313-330.Abstract
Mucins are a family of high molecular weight, heavily-glycosylated proteins produced by wet epithelial tissues, including the ocular surface epithelia. Densely-packed O-linked glycan chains added post-translationally confer the biophysical properties of hydration, lubrication, anti-adhesion and repulsion. Membrane-associated mucins (MAMs) are the distinguishing components of the mucosal glycocalyx. At the ocular surface, MAMs maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world. In addition, it is increasingly appreciated that MAMs function as cell surface receptors that transduce information from the outside to the inside of the cell. Recently, our team published a comprehensive review/perspectives article for molecular scientists on ocular surface MAMs, including previously unpublished data and analyses on two new genes MUC21 and MUC22, as well as new MAM functions and biological roles, comparing human and mouse (PMID: 31493487). The current article is a refocus for the audience of The Ocular Surface. First, we update the gene and protein information in a more concise form, and include a new section on glycosylation. Next, we discuss biological roles, with some new sections and further updating from our previous review. Finally, we provide a new chapter on MAM involvement in ocular surface disease. We end this with discussion of an emerging mechanism responsible for damage to the epithelia and their mucosal glycocalyces: the unfolded protein response (UPR). The UPR offers a novel target for therapeutic intervention.
Dohlman TH, Singh RB, Dana R. Advances in the Medical Management of Neurotrophic Keratitis. Semin Ophthalmol 2021;36(4):335-340.Abstract
Neurotrophic Keratitis (NK) is a degenerative disorder of the cornea characterized by decreased or absent sensory corneal innervation, corneal epitheliopathy and impaired healing.The clinical presentation of NK can range from persistent epithelial defects to corneal perforation and management is often both challenging and protracted. Historically, the management of NK has consisted of non-specific strategies to facilitate corneal epithelial healing such as lubrication, bandage contact lenses and tarsorrhaphy. Recent advances in the development of therapeutics for NK have provided new and efficacious targeted strategies for its management.In this article, we review recombinant human nerve growth factor (Cenegermin), currently approved for clinical use in the United States and Europe, as well as other promising therapeutic options that are in pre-clinical development such as thymosine β4, connexin43 inhibitors, and artificial extracellular matrix components.
Sharifi S, Islam MM, Sharifi H, Islam R, Huq TN, Nilsson PH, Mollnes TE, Tran KD, Patzer C, Dohlman CH, Patra HK, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Electron Beam Sterilization of Poly(Methyl Methacrylate)-Physicochemical and Biological Aspects. Macromol Biosci 2021;21(4):e2000379.Abstract
Electron beam (E-beam) irradiation is an attractive and efficient method for sterilizing clinically implantable medical devices made of natural and/or synthetic materials such as poly(methyl methacrylate) (PMMA). As ionizing irradiation can affect the physicochemical properties of PMMA, understanding the consequences of E-beam sterilization on the intrinsic properties of PMMA is vital for clinical implementation. A detailed assessment of the chemical, optical, mechanical, morphological, and biological properties of medical-grade PMMA after E-beam sterilization at 25 and 50 kiloGray (kGy) is reported. Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry studies indicate that E-beam irradiation has minimal effect on the chemical properties of the PMMA at these doses. While 25 kGy irradiation does not alter the mechanical and optical properties of the PMMA, 50 kGy reduces the flexural strength and transparency by 10% and 2%, respectively. Atomic force microscopy demonstrates that E-beam irradiation reduces the surface roughness of PMMA in a dose dependent manner. Live-Dead, AlamarBlue, immunocytochemistry, and complement activation studies show that E-beam irradiation up to 50 kGy has no adverse effect on the biocompatibility of the PMMA. These findings suggest that E-beam irradiation at 25 kGy may be a safe and efficient alternative for PMMA sterilization.
Moein H-R, Sendra VG, Jamali A, Kheirkhah A, Harris DL, Hamrah P. Herpes simplex virus-1 KOS-63 strain is virulent and causes titer-dependent corneal nerve damage and keratitis. Sci Rep 2021;11(1):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 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. Naïve, 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 ×) and neovascularization (2.6 × ; 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 naïve 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 naïve 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.

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