Activation of cGAS-dependent antiviral responses by DNA intercalating agents

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)- dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells.

Original languageEnglish
Pages (from-to)198-205
Number of pages8
JournalNucleic Acids Research
Volume45
Issue number1
DOIs
Publication statusPublished - 9 Jan 2017

Cite this

@article{555411705e1f47de83b39c79c5eb67e5,
title = "Activation of cGAS-dependent antiviral responses by DNA intercalating agents",
abstract = "Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)- dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells.",
author = "Genevieve Pepin and Charlotte Nejad and Thomas, {Belinda J.} and Jonathan Ferrand and Kate McArthur and Bardin, {Philip G.} and Williams, {Bryan R G} and Gantier, {Michael P.}",
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language = "English",
volume = "45",
pages = "198--205",
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publisher = "Oxford University Press",
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Activation of cGAS-dependent antiviral responses by DNA intercalating agents. / Pepin, Genevieve; Nejad, Charlotte; Thomas, Belinda J.; Ferrand, Jonathan; McArthur, Kate; Bardin, Philip G.; Williams, Bryan R G; Gantier, Michael P.

In: Nucleic Acids Research, Vol. 45, No. 1, 09.01.2017, p. 198-205.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of cGAS-dependent antiviral responses by DNA intercalating agents

AU - Pepin, Genevieve

AU - Nejad, Charlotte

AU - Thomas, Belinda J.

AU - Ferrand, Jonathan

AU - McArthur, Kate

AU - Bardin, Philip G.

AU - Williams, Bryan R G

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AB - Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)- dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells.

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