Abstract
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.
Highlights
Vesicular stomatitis virus (VSV) is a non-segmented negativestranded RNA virus that belongs to the family rhabdoviridae [1]
The identification of double-stranded triphosphate RNA as the pathogen associated molecular pattern (PAMP) detected by retinoic acid-inducible gene I (RIG-I) posed the question which RNA species in the replication cycle of the different RIG-Irestricted viruses are the relevant, naturally occurring ligands
Extensively studied as a model for mononegavirales biology and being developed as an instrument for vaccines and oncolytic therapy, the RIG-I ligands occurring during infection with VSV have not been clarified
Summary
Vesicular stomatitis virus (VSV) is a non-segmented negativestranded RNA virus that belongs to the family rhabdoviridae [1] It is characterized by a simple structure, the ability to tolerate additional transcriptional units, rapid replication kinetics in mammalian and many other cell types and no relevant clinical pathology in humans. The sustained Ebola GP-specific antibody response induced by the vaccine thereby correlates with an early activation of innate immunity, especially of type-I interferon induced genes [3, 4] This highlights that VSV-based replication-competent vaccines do provide a delivery system for the antigen of interest, but serve as an intrinsic adjuvant by stimulating innate immunity. Driven by the success against Ebola several companies and academic groups work on VSV-based COVID-19 vaccines for the ongoing SARS-CoV-2 pandemic
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