Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany.
Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.
Front Immunol. 2021 Apr 30;12:595390. doi: 10.3389/fimmu.2021.595390. eCollection 2021.
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 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.
复制型水疱性口炎病毒（VSV）是埃博拉疫苗的基础，VSV 株被开发为溶瘤病毒。这两种功能都依赖于 VSV 诱导足够量干扰素-α/β的能力。因此，了解 VSV 如何触发干扰素反应非常重要。VSV 通过激活先天免疫的视黄酸诱导基因 I（RIG-I）来识别病毒 RNA。我们的结果表明，VSV 需要复制才能产生强烈的干扰素反应。对与 RIG-I 相关的 RNA 的分析确定了反向互补缺陷干扰（DI）基因组和全长病毒基因组是 RIG-I 的主要触发因素。缺乏 DI 基因组的 VSV 株失去了大部分干扰素刺激活性。然而，剩余的全长基因组和前导-N 通读序列仍然可以触发 RIG-I。认识到 DI 基因组作为先天免疫反应的触发因素将有助于规范 DI 基因组的含量，并有意地在基于 VSV 的治疗中使用 DI 基因组作为天然佐剂。
