ASMicro 2018 Modulation of antiviral responses by low dose-DNA damaging agents (#81)
Topoisomerase I (top1) inhibition relying on low-dose Camptothecin (CPT) has recently been proposed to show interesting therapeutic potential to dampen cytokine storms associated with high morbidity upon viral infections (Science, 2016 352(6289):aad7993), for its capacity to block transcription of pro-inflammatory factors. Critically, CPT also impairs the DNA repair machinery and results in DNA damage. In light of accumulating evidence demonstrating that nuclear DNA damage can result in antiviral activation through engagement of the cytosolic cGAS-STING pathway, we investigated the effect of low-dose CPT on innate immune responses (1). We discovered that minor DNA damage from top1 inhibition with low-dose CPT could trigger a strong antiviral immune response through cyclic GMP–AMP synthase (cGAS) detection of cytoplasmic DNA, but that this was dependent on the presence of viral oncogenes. Conversely, dual top1/2 inhibition by acriflavine (2) could result in antiviral effects independent of such viral oncogenes. Our work demonstrates that the mechanism of how DNA damage engages antiviral responses is more complex than previously proposed, and calls for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans.
- Pépin G, Nejad C, Ferrand J, Thomas BJ, Stunden HJ, Sanij E, Foo CH, Stewart CR, Cain JE, Bardin PG, Williams BRG, Gantier MP. Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses. MBio. 2017 8(5). pii: e01611-17. doi: 10.1128/mBio.01611-17.
- Pépin G, Nejad C, Thomas BJ, Ferrand J, McArthur K, Bardin PG, Williams BR, Gantier MP. Activation of cGAS-dependent antiviral responses by DNA intercalating agents. Nucleic Acids Res. 2017 45(1):198-205. doi: 10.1093/nar/gkw878.
