Innate Immune Priming by cGAS as a Preparatory Countermeasure Against RNA Virus Infection

Michael T. Parker; Smita Gopinath; Corey E. Perez; Melissa M. Linehan; Jason M. Crawford; Akiko Iwasaki; Brett D. Lindenbach

Because cGAS DNA binding activity was required for VSV restriction, we 335 examined whether VSV introduces cGAS DNA ligands into the cytosol. Prior work 336 has shown that the cytosolic release of mtDNA activates the cGAS-STING pathway 337 (33-35); moreover, infection with HSV-1, a DNA virus, or dengue virus, an RNA 338 virus, reportedly causes cytosolic release of mtDNA (34, 40). An emerging concept 339 is that mammalian cells may regulate the efflux of mtDNA into the cytosol in 340 response to stress, supported by a role for the Bax/Bak pore in mtDNA release as 341 well as mitochondrial inner membrane release mechanisms via permeabilization and 342 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/434027 doi: bioRxiv preprint herniation (33-35, 54, 55) . In contrast, the levels of cytosolic mtDNA and 343 cGAS-associated mtDNA did not increase during VSV infection. Moreover, 344 cGAS-STING-mediated VSV restriction was intact in  0 cells, which lack mtDNA, 345 consistent with similar experiments reported by Franz et al. (20) . Real-time 346 examination of mitochondrial dynamics may be needed to clarify the role of mtDNA 347 release during RNA virus infections. 348