Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses

ABSTRACT Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and...

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Autores principales:	Geneviève Pépin, Charlotte Nejad, Jonathan Ferrand, Belinda J. Thomas, H. James Stunden, Elaine Sanij, Chwan-Hong Foo, Cameron R. Stewart, Jason E. Cain, Philip G. Bardin, Bryan R. G. Williams, Michael P. Gantier
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	DNA damage STING cGAS camptothecin simian virus 40 topoisomerase 1 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1854a7e1960c44029afa2f6f6b8c9dcb
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spelling	oai:doaj.org-article:1854a7e1960c44029afa2f6f6b8c9dcb2021-11-15T15:51:51ZTopoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses10.1128/mBio.01611-172150-7511https://doaj.org/article/1854a7e1960c44029afa2f6f6b8c9dcb2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01611-17https://doaj.org/toc/2150-7511ABSTRACT Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40) large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development. IMPORTANCE Recent studies suggest that low-dose DNA-damaging compounds traditionally used in cancer therapy can have opposite effects on antiviral responses, either suppressing (with the example of CPT) or potentiating (with the example of doxorubicin) them. Our work demonstrates that the minor DNA damage promoted by low-dose CPT can also trigger strong antiviral responses, dependent on the presence of viral oncogenes. Taken together, these results call for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans.Geneviève PépinCharlotte NejadJonathan FerrandBelinda J. ThomasH. James StundenElaine SanijChwan-Hong FooCameron R. StewartJason E. CainPhilip G. BardinBryan R. G. WilliamsMichael P. GantierAmerican Society for MicrobiologyarticleDNA damageSTINGcGAScamptothecinsimian virus 40topoisomerase 1MicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA damage STING cGAS camptothecin simian virus 40 topoisomerase 1 Microbiology QR1-502
spellingShingle	DNA damage STING cGAS camptothecin simian virus 40 topoisomerase 1 Microbiology QR1-502 Geneviève Pépin Charlotte Nejad Jonathan Ferrand Belinda J. Thomas H. James Stunden Elaine Sanij Chwan-Hong Foo Cameron R. Stewart Jason E. Cain Philip G. Bardin Bryan R. G. Williams Michael P. Gantier Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
description	ABSTRACT Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40) large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development. IMPORTANCE Recent studies suggest that low-dose DNA-damaging compounds traditionally used in cancer therapy can have opposite effects on antiviral responses, either suppressing (with the example of CPT) or potentiating (with the example of doxorubicin) them. Our work demonstrates that the minor DNA damage promoted by low-dose CPT can also trigger strong antiviral responses, dependent on the presence of viral oncogenes. Taken together, these results call for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans.
format	article
author	Geneviève Pépin Charlotte Nejad Jonathan Ferrand Belinda J. Thomas H. James Stunden Elaine Sanij Chwan-Hong Foo Cameron R. Stewart Jason E. Cain Philip G. Bardin Bryan R. G. Williams Michael P. Gantier
author_facet	Geneviève Pépin Charlotte Nejad Jonathan Ferrand Belinda J. Thomas H. James Stunden Elaine Sanij Chwan-Hong Foo Cameron R. Stewart Jason E. Cain Philip G. Bardin Bryan R. G. Williams Michael P. Gantier
author_sort	Geneviève Pépin
title	Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
title_short	Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
title_full	Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
title_fullStr	Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
title_full_unstemmed	Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
title_sort	topoisomerase 1 inhibition promotes cyclic gmp-amp synthase-dependent antiviral responses
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/1854a7e1960c44029afa2f6f6b8c9dcb
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Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses

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