Inhibition of the DNA damage response blocks herpes simplex virus infection in corneal epithelium

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Abstract

Purpose

Herpes simplex keratitis (HSK) is the leading cause of cornea-derived and infection-associated blindness in the developed world. Many HSK cases are refractory to treatment with available drugs, leading to permanent corneal pathology. In addition, drug-resistant viral strains are beginning to emerge and may present a major clinical problem in the future. Thus, our study focused on identifying and targeting critical virus-host interactions to suppress herpes simplex virus (HSV) infection in corneal epithelium. Specifically, we investigated the role of ataxia telangiectasia mutated (ATM), a key protein in the mammalian DNA damage response pathway, in the molecular pathogenesis of HSK.

Methods

We utilized three experimental models in our studies. The in vitro model (human corneal epithelial and keratinocyte cell lines) was used to dissect the molecular mechanisms of HSV-ATM interactions. The ex vivo model (human and rabbit explanted corneas) was used to validate our tissue culture findings. And the in vivo model (young C57BL/6 mice) was used to test the antiviral potential of ATM inhibition in a physiologically-relevant context of ocular infection.

Results

ATM inhibition reduces HSV infection in corneal epithelial cells by blocking viral genome replication. Importantly, this inhibitory effect was observed not only with wild type HSV-1, but also with two different drug-resistant strains. The antiviral effects of Acyclovir and ATM inhibition were additive. We have also made progress into elucidating the molecular mechanisms underlying this phenomenon.

Conclusion

We have shown that ATM is a new therapeutic target for the treatment of herpes simplex keratitis. ATM inhibitors could be used alone or as adjuvant therapy to combat HSK.

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