DNA is potently immunostimulatory, and self-DNA is packaged in the nucleus or mitochondria allowing it to remain silent to cell-intrinsic sensors. However, damaged or mislocalised self-DNA is sensed by our innate immune systems, resulting in the production of type I interferons (IFNI), chemokines and inflammatory cytokines. During DNA virus infection the detection of viral DNA genomes by pattern recognition receptors (PRRs) is essential for the initiation of IFNI responses and host defence against these pathogens. It is intriguing that a number of molecular mechanisms have been found to be common to both of these DNA-induced stress responses and this has potentially important consequences for both sides of the host/pathogen arms race.
Zika virus (ZIKV) is a single-strand RNA mosquito-borne flavivirus with significant public health impact. ZIKV infection induces double-strand DNA breaks (DSBs) in human neural progenitor cells that may contribute to severe neuronal manifestations in newborns. The DNA-PK complex plays a critical role in repairing DSBs and in the innate immune response to infection. It is unknown, however, whether DNA-PK regulates ZIKV infection. Here we investigated the role of DNA-PKcs, the catalytic subunit of DNA-PK, during ZIKV infection. We demonstrate that DNA-PKcs restricts the spread of ZIKV infection in human epithelial cells. Increased ZIKV replication and spread in DNA-PKcs deficient cells is related to a notable decrease in transcription of type I and III interferons as well as IFIT1, IFIT2, and IL6. This was shown to be independent of IRF1, IRF3, or p65, canonical transcription factors necessary for activation of both type I and III interferon promoters. The mechanism of DNA-PKcs to restrict ZIKV infection is independent of DSB. Thus, these data suggest a non-canonical role for DNA-PK during Zika virus infection, acting downstream of IFNs transcription factors for an efficient antiviral immune response.
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