Early events in HSV keratitis—setting the stage for a blinding disease

Biswas, Partha S.; Rouse, Barry T.

doi:10.1016/j.micinf.2005.03.003

Cited by 167 publications

(234 citation statements)

References 96 publications

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“…13,31 Previously, we reported that HSV-1 causes regression of sensory fibers innervating the cornea and loss of their function during the acute phase of infection, followed by abnormal nerve regeneration at a time point consistent with establishment of viral latency. 23 Since 8 days pi, the time point pi of maximal observed loss of innervation, coincides with a highly inflammatory milieu in the infected cornea, 12,14 we hypothesized the mechanism triggering regression of corneal nerves is immune system mediated. To test this hypothesis, we evaluated the effects of DEX, a clinically prescribed, anti-inflammatory reagent, 25,26 on the corneal nerve network after HSV-1 infection.…”

Section: Dex Prevents Corneal Nerve Regression and Sensation Loss Aftmentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1einduced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression.

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Section: Dex Prevents Corneal Nerve Regression and Sensation Loss Aftmentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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“…Infection begins in peripheral epithelial tissues, including the oral mucosal, skin, or corneal epithelium. After replicating in the epithelium, the virus infects adjacent neurons and travels via retrograde transport to sensory ganglia, including the trigeminal ganglia (TG) (1). In nerve cell bodies HSV is able to establish a life-long latent infection and reactivate at a later point or immediately undergo additional rounds of replication.…”

mentioning

confidence: 99%

Herpesvirus Entry Mediator and Nectin-1 Mediate Herpes Simplex Virus 1 Infection of the Murine Cornea

Karaba

Kopp

Longnecker

2011

J Virol

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Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that enters cells by the receptor-mediated fusion of the viral envelope with a host cell membrane. The envelope glycoprotein gD of HSV must bind to one of its receptors for entry to take place. Recent studies using knockout (KO) mice demonstrated that the gD receptors herpesvirus entry mediator (HVEM) and nectin-1 are the primary entry receptors for HSV-2 in the mouse vagina and brain. Nectin-1 was most crucial for the neuronal spread of HSV-2, particularly in the brain. HVEM was dispensable for infection in these models, but when both HVEM and nectin-1 were absent, infection was completely prevented. We sought to determine the receptor requirements of HSV-1 in an ocular model of infection using knockout mice. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double-KO mice were infected via corneal scarification and monitored for clinical signs of infection and viral replication in various tissues. We report that either HVEM or nectin-1 must be present for HSV-1 infection of the cornea. Additionally, we observed that the infection was attenuated in both HVEM KO and nectin-1 KO mice. This is in contrast to what was reported for studies of HSV-2 in vagina and brain and suggests that receptor requirements for HSV vary depending on the route of inoculation and/or serotype.Herpes simplex virus 1 (HSV-1), an alphaherpesvirus, is the leading cause of infectious blindness in developed countries (12). Infection begins in peripheral epithelial tissues, including the oral mucosal, skin, or corneal epithelium. After replicating in the epithelium, the virus infects adjacent neurons and travels via retrograde transport to sensory ganglia, including the trigeminal ganglia (TG) (1). In nerve cell bodies HSV is able to establish a life-long latent infection and reactivate at a later point or immediately undergo additional rounds of replication. During replication in neurons the virus can transit back down axons and reinfect the site of inoculation. HSV is also capable of spreading, in a zosteriform manner, to other peripheral tissues innervated by neurons from the infected ganglia. In rare cases in humans the virus can spread to the brain and cause encephalitis (7). HSV-1 is the predominant cause of ocular herpes infections and usually begins as conjunctivitis or epithelial keratitis. The reactivation of the virus can lead to subsequent damage to the cornea and stromal keratitis. This outcome depends on a variety of host and viral factors but often leads to blindness (2).The infectious cycle of HSV-1 begins when the virion envelope fuses with a host cell membrane either at the plasma membrane or in endocytic vesicles. Fusion is a complex process that requires multiple glycoproteins, including gD, gB, and the heterodimeric complex gH/gL (4). While the precise function of each glycoprotein remains unclear, it is well accepted that gD must bind to a gD receptor on the host cell for efficient entry. Several gD receptors have been identified, including herpesvirus entry ...

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“…During the course of herpetic keratitis, the HSV-induced cytopathogenicity together with the chronic immune-inflammatory reaction can trigger stromal scarring, thinning and neovascularization, leading to permanent vision impairment. Herpetic keratitis therefore remains a frequent infectious cause of blindness in many countries (Biswas and Rouse 2005;Choudhary et al 2008;Rowe et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Systemic and local stressors can interrupt the latency and induce viral reactivation, leading to recrudescent infections. The cytopathogenic mechanism of diseases caused by HSV-1 and HSV-2 involves indirect, immune processes and direct, virus-mediated events (Biswas and Rouse 2005;Holdeman 2005; Kaye and Choudhary 2006;Fatahzadeh and Schwartz 2007;Choudhary et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex virus types 1 and 2 modulate autophagy in SIRC corneal cells

et al. 2014

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Autophagy and apoptosis function as important early cellular defense mechanisms in infections and other diseases. The outcome of an infection is determined by a complex interplay between the pathogenic microorganism and these intracellular pathways. To better understand the cytopathogenicity of Herpes simplex virus types 1 and 2 (HSV-1 and -2), we studied the effect of these viruses on the autophagic and apoptotic processes in the SIRC corneal cell line. Infection with the KOS strain of HSV-1 and a wild-type strain of HSV-2 enhanced autophagosome formation, triggered cytoplasmic acidification, increased LC3B lipidation and elevated the ratio of apoptotic cells. The autophagy inhibitor bafilomycin A1 triggered a significant increase in the apoptotic responses of HSV-1-and HSV-2-infected cells. Thus, both HSV types affect autophagy and apoptosis in a coordinated fashion, and autophagy plays cytoprotective role in HSV-infected cells via antagonizing apoptosis. Together these data implicate autophagy in the pathogenic mechanism of herpetic keratitis.[Petrovski G, Pásztor K, Orosz L, Albert R, Mencel E, Moe MC, Kaarniranta K, Facskó A and Megyeri K 2014 Herpes simplex virus types 1 and 2 modulate autophagy in SIRC corneal cells.

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Early events in HSV keratitis—setting the stage for a blinding disease

Cited by 167 publications

References 96 publications

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Herpesvirus Entry Mediator and Nectin-1 Mediate Herpes Simplex Virus 1 Infection of the Murine Cornea

Herpes simplex virus types 1 and 2 modulate autophagy in SIRC corneal cells

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