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MBio. 2017 Oct 3;8(5). pii: e01611-17. doi: 10.1128/mBio.01611-17.

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

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
2
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
3
Monash Lung and Sleep, Monash Medical Centre, Clayton, Victoria, Australia.
4
Institute of Innate Immunity, Biomedical Center, University Hospitals Bonn, Bonn, Germany.
5
Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
6
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
7
CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
8
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
9
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia michael.gantier@hudson.org.au.

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.

KEYWORDS:

DNA damage; STING; cGAS; camptothecin; simian virus 40; topoisomerase 1

PMID:
28974621
PMCID:
PMC5626974
DOI:
10.1128/mBio.01611-17
[Indexed for MEDLINE]
Free PMC Article

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