Inhibition of Ataxia Telangiectasia Mutated (ATM) Kinase Suppresses Herpes Simplex Virus Type 1 (HSV-1) Keratitis

Alekseev, Oleg; Donovan, Kelly; Azizkhan‐Clifford, Jane

doi:10.1167/iovs.13-13461

Cited by 25 publications

(27 citation statements)

References 55 publications

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“…Work is continuous, but it appears that promising opportunities are being identified. Alekseev et al 203 have recently identified a kinase, ataxia telangiectasia mutated (ATM) kinase, whose inhibition reduces the severity of keratitis in a mouse model of HSV1 keratitis and additionally slows viral replication in rabbit and human cultured corneas. A high-affinity human monoclonal antibody to S. aureus α-toxin has been found to be effective at reducing corneal damage 204 and a new antibiotic, targocil, has had some preliminary success at inhibiting the severity of staphylococcal infections.…”

Section: Potential Targeted Molecular Therapiesmentioning

confidence: 99%

Pattern recognition receptors in microbial keratitis

Taube

Cendra

Elsahn

et al. 2015

Eye

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Section: Potential Targeted Molecular Therapiesmentioning

confidence: 99%

Pattern recognition receptors in microbial keratitis

Taube

Cendra

Elsahn

et al. 2015

Eye

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“…Since the original discovery that placed this kinase within the host DNA damage response network, ATM has been recognized as a key player in several additional cellular signaling networks that include oxidative stress, metabolism, angiogenesis, and mitophagy (reviewed in (Guleria & Chandna, 2016)). Intriguingly, this kinase also supports replication of multiple diverse DNA and RNA viruses, including but not limited to human and mouse gammaherpesviruses (Hagemeier, Barlow et al, 2012; Singh, Dutta et al, 2013; Tarakanova, Leung-Pineda et al, 2007), alpha- and beta herpesviruses (E X, Pickering et al, 2011; Alekseev, Donovan et al, 2014), papilloma- and polyomaviruses (Moody & Laimins, 2009; Tsang, Wang et al, 2014; Jiang, Zhao et al, 2012), adenovirus (Shah & O’Shea, 2015), HCV (Ariumi, Kuroki et al, 2008), and HIV (Lau, Swinbank et al, 2005). The functions of ATM in the DNA damage response have traditionally been assumed as the mechanism underlying the proviral activity of this kinase.…”

Section: Introductionmentioning

confidence: 99%

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

et al. 2017

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Ataxia-Telangiectasia mutated (ATM) kinase participates in multiple networks, including DNA damage response, oxidative stress, and mitophagy. ATM also supports replication of diverse DNA and RNA viruses. Gammaherpesviruses are prevalent cancer-associated viruses that benefit from ATM expression during replication. This proviral role of ATM had been ascribed to its signaling within the DNA damage response network; other functions of ATM have not been considered. In this study increased type I interferon (IFN) responses were observed in ATM deficient gammaherpesvirus-infected macrophages. Using a mouse model that combines ATM and type I IFN receptor deficiencies we show that increased type I IFN response in the absence of ATM fully accounts for the proviral role of ATM during gammaherpesvirus replication. Further, increased type I IFN response rendered ATM deficient macrophages more susceptible to antiviral effects of type II IFN. This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection.

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“…Cellular DDR proteins are also possible candidates for treatment of acute HSV-1 infection. For example, the ATM inhibitor, KU-55933 has recently been shown to suppress HSV-1 replication and cytopathic effects in herpes keratitis [112]. The observation that several DDR proteins are important antiviral modulators may also be exploited in the future for novel antiviral strategies.…”

Section: The Future Outlook Of Hsv-1 and Cellular Ddr Researchmentioning

confidence: 99%

HSV-I and the Cellular DNA Damage Response

Smith

Weller

2015

Future Virol.

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Peter Wildy first observed genetic recombination between strains of HSV in 1955. At the time, knowledge of DNA repair mechanisms was limited, and it has only been in the last decade that particular DNA damage response (DDR) pathways have been examined in the context of viral infections. One of the first reports addressing the interaction between a cellular DDR protein and HSV-1 was the observation by Lees-Miller et al. that DNA-dependent protein kinase catalytic subunit levels were depleted in an ICP0-dependent manner during Herpes simplex virus 1 infection. Since then, there have been numerous reports describing the interactions between HSV infection and cellular DDR pathways. Due to space limitations, this review will focus predominantly on the most recent observations regarding how HSV navigates a potentially hostile environment to replicate its genome.

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Inhibition of Ataxia Telangiectasia Mutated (ATM) Kinase Suppresses Herpes Simplex Virus Type 1 (HSV-1) Keratitis

Cited by 25 publications

References 55 publications

Pattern recognition receptors in microbial keratitis

Pattern recognition receptors in microbial keratitis

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

HSV-I and the Cellular DNA Damage Response

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