Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation

doi:10.1016/j.jtos.2018.10.002

The Ocular Surface

Volume 17, Issue 1, January 2019, Pages 40-49

https://doi.org/10.1016/j.jtos.2018.10.002 Get rights and content

Abstract

Herpes simplex virus type 1 (HSV) keratitis is a leading cause of infectious blindness. Clinical disease occurs variably throughout the cornea from epithelium to endothelium and recurrent HSV stromal keratitis is associated with corneal scarring and neovascularization. HSV keratitis can be associated with ocular pain and subsequent neutrophic keratopathy. Host cell interactions with HSV trigger an inflammatory cascade responsible not only for clearance of virus but also for progressive corneal opacification due to inflammatory cell infiltrate, angiogenesis, and corneal nerve loss. Current antiviral therapies target viral replication to decrease disease duration, severity and recurrence, but there are limitations to these agents. Therapies directed towards viral entry into cells, protein synthesis, inflammatory cytokines and vascular endothelial growth factor pathways in animal models represent promising new approaches to the treatment of recurrent HSV keratitis.

Section snippets

Herpes keratitis

Herpes simplex virus type 1 (HSV) is the leading cause of infectious blindness in the developed world. HSV infection can occur at any location in the eye; the most common presentation is epithelial or dendritic keratitis. Herpes stromal keratitis can result in progressive corneal opacification and vision loss with recurrent disease. The host cell's response to HSV plays an important role in the pathogenesis of HSV infection in the eye. Novel therapeutics targeting these host cell interactions

Overview of pathophysiology

In order for HSV to cause clinical signs of infection in the cornea, it must evade the multiple barriers created by the host, including the innate immune response early in disease and the subsequent delayed adaptive immune response resulting from viral antigen presentation. HSV gains entry to corneal epithelial cells through interaction of specific viral and host receptors. HSV uses host cell DNA polymerase to replicate and create viral progeny which then exit the cell and move on to infect

Antiviral

Current antiviral therapy for HSV is targeted to inhibition of viral replication. Three systemic (acyclovir, valacyclovir and famciclovir) and two topical (trifluridine and ganciclovir gel) therapies are currently available in the United States for HSV infection, although only the topical therapies are approved by the FDA specifically for the treatment of HSV keratitis [125]. Acyclovir is available in topical form in Europe and other countries. Acyclovir is a nucleoside analog that inhibits DNA

Conclusions

The host cell responds to HSV infection with a complex series of events of immunopathogenesis, manifesting as either epithelial, stromal, or endothelial keratitis. Innate and adaptive immune responses are responsible for clearing active HSV infection, but also cause damaging inflammation within the cornea which can lead to neovascularization and scarring. While antiviral and anti-inflammatory therapies help to reduce the duration, severity and risk for recurrent HSV keratitis, there are

Funding

Supported by grants: P30 EY001792 (AML, AMA, DS), NIH/NEI K12 EY021475 (AML), NIH/NEI R01 EY024710-A1 and R01 EY029426 (DS), NIH/NIAID R21AI128171-01A1 (DS), unrestricted departmental funding from Research to Prevent Blindness (AML, AMA, DS).

Conflicts of interest

The authors report no conflicts of interest or disclosures for this manuscript submission.

Acknowledgments

The authors would like to thank Ms. Margaret Chervinko, MFA, MLIS, and Ms. Safa Arfeen for their assistance with literature searches for this review.

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View full text

Review ArticlePathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation

Abstract

Section snippets

Herpes keratitis

Overview of pathophysiology

Antiviral

Conclusions

Funding

Conflicts of interest

Acknowledgments

Surv Ophthalmol

Ophthalmology

Surv Ophthalmol

Prog Retin Eye Res

Exp Eye Res

Immunity

Virus Res

Prog Retin Eye Res

Am J Pathol

Immunity

Immunity

J Mol Biol

J Biomed Res

Microb Infect

Exp Eye Res

Matrix Biol

Cell Rep

Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry

J Clin Invest

Cell entry mechanisms of HSV: what we have learned in recent years

Future Virol

Heparanase is a host enzyme required for herpes simplex virus-1 release from cells

Nat Commun

Seroprevalence of herpes simplex virus types 1 and 2--United States, 1999-2010

J Infect Dis

Prevalence of antibodies against herpes simplex virus types 1 and 2 in children and young people in an urban region in Tanzania

J Clin Microbiol

Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis

Arch Ophthalmol

Herpes simplex virus epidemiology and ocular importance

Cornea

Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases

Bioessays

Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice

J Virol

Herpes simplex of the ocular anterior segment

Curr Clin Top Infect Dis

Bilateral herpetic keratitis after bilateral intravitreal bevacizumab for exudative macular degeneration

Cornea

Epidemiological and clinical features of primary herpes simplex virus ocular infection

Br J Ophthalmol

Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982

Arch Ophthalmol

Human herpes simplex virus keratitis: the pathogenesis revisited

Ocul Immunol Inflamm

Classification of herpes simplex virus keratitis and anterior uveitis

Cornea

Early epithelial changes in recurrent herpes simplex virus keratitis: a non-contact photomicrographic study in vivo in the human cornea

Acta Ophthalmol Scand

Cultured corneas show dendritic spread and restrict herpes simplex virus infection that is not observed with cultured corneal cells

Sci Rep

Macrophages and cytokines in the early defence against herpes simplex virus

Virol J

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Proc Natl Acad Sci U S A

Herpetic keratitis: persistence of viral particles despite topical and systemic antiviral therapy. Report of two cases and review of the literature

Arch Ophthalmol

Virological and molecular biological evidence supporting herpes simplex virus type 1 corneal latency

Jpn J Ophthalmol

Review of clinical and basic approaches to corneal endotheliitis

Cornea

Endothelial involvement in herpes simplex virus keratitis: an in vivo confocal microscopy study

Ophthalmology

On the essential involvement of neutrophils in the immunopathologic disease: herpetic stromal keratitis

J Immunol

Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea

J Virol

Novel characterization of MHC class II-negative population of resident corneal Langerhans cell-type dendritic cells

Invest Ophthalmol Vis Sci

Corneal immunity is mediated by heterogeneous population of antigen-presenting cells

Review Article
Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation