Replication competent vesicular stomatitis virus (VSV) is the basis of a vaccine against Ebola and VSV strains are developed as oncolytic viruses. Both functions depend on the ability of VSV to induce adequate amounts of interferon-α/β. It is therefore important to understand how VSV triggers interferon responses. VSV activates innate immunity via retinoic acid-inducible gene I (RIG-I), a sensor for viral RNA. Our results show that VSV needs to replicate for a robust interferon response. Analysis of RIG-I-associated RNA identified a copy-back defective-interfering (DI) genome and full-length viral genomes as main trigger of RIG-I. VSV stocks depleted of DI genomes lost most of their interferon-stimulating activity. The remaining full-length genome and leader-N-read-through sequences, however, still triggered RIG-I. Awareness for DI genomes as trigger of innate immune responses will help to standardize DI genome content and to purposefully deplete or use DI genomes as natural adjuvants in VSV-based therapeutics.
Keywords: defective interfering genome; nucleic acid sensing; pathogen associated molecular pattern (PAMP); pattern recognition receptor (PRR); retinoid acid inducible gene I (RIG-I); vesicular stomatitis virus (VSV).
Copyright © 2021 Linder, Bothe, Linder, Schwarzlmueller, Dahlström, Bartenhagen, Dugas, Pandey, Thorn-Seshold, Boehmer, Koenig, Kobold, Schnurr, Raedler, Spielmann, Karimzadeh, Schmidt, Endres and Rothenfusser.