Activation of cGAS-dependent antiviral responses by DNA intercalating agents.
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.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
Geneviève
G
Pépin
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
Charlotte
C
Nejad
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.|Monash Lung and Sleep, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Belinda J
BJ
Thomas
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
Jonathan
J
Ferrand
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
Kate
K
McArthur
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.|Monash Lung and Sleep, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Philip G
PG
Bardin
Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.|Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
Bryan R G
BR
Williams
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia michael.gantier@hudson.org.au.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
Michael P
http://orcid.org/0000-0003-3740-698X
MP
Gantier
D000167:Acriflavine / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology*; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009712:Nucleotides, Cyclic / Q000276:immunology / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000276:immunology; D061251:Primary Cell Culture; D011370:Proflavine / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects / Q000254:growth & development; D015398:Signal Transduction; D014709:Vero Cells; D019562:Viral Load / Q000187:drug effects; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D000167:Acriflavine; D000998:Antiviral Agents; D007155:Immunologic Factors; D007364:Intercalating Agents; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D011370:Proflavine; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
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