Defective Interfering Genomes and the Full-Length Viral Genome Trigger RIG-I After Infection With Vesicular Stomatitis Virus in a Replication Dependent Manner

Linder, A., Bothe, V., Linder, N., Schwarzlmueller, P., Dahlstrom, F., Bartenhagen, C., Dugas, M., Pandey, D., Thorn-Seshold, J., Boehmer, D. F. R., Koenig, L. M., Kobold, S., Schnurr, M., Raedler, J., Spielmann, G., Karimzadeh, H., Schmidt, A., Endres, S., and Rothenfusser, S. (2021). Front Immunol 12, 595390. doi: 10.3389/fimmu.2021.595390


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.