RIG-I and MDA-5 Detection of Viral RNA-dependent RNA Polymerase Activity Restricts Positive-Strand RNA Virus Replication

PLoS Pathogens

Andrei Nikonov¹  Tarmo Mölder¹  Mart Ustav¹  Rein Sikut²  Kaja Kiiver²  Age Utt²  Andres Männik²  Aleksei Lulla²  Urve Toots³  Valeria Lulla³  Andres Merits³ 

[1] Department of Biomedical Technology, Institute of Technology, University of Tartu, Tartu, Estonia;FIT Biotech Oy, Tartu, Estonia;Icosagen Cell Factory OÜ, Tartu, Estonia

关键词: Viral replication;    RNA extraction;    dsRNA viruses;    Host cells;    RNA isolation;    Small interfering RNAs;    Transfection;    Ribonucleases;   

DOI  :  10.1371/journal.ppat.1003610

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Type I interferons (IFN) are important for antiviral responses. Melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-induced gene I (RIG-I) proteins detect cytosolic double-stranded RNA (dsRNA) or 5′-triphosphate (5′-ppp) RNA and mediate IFN production. Cytosolic 5′-ppp RNA and dsRNA are generated during viral RNA replication and transcription by viral RNA replicases [RNA-dependent RNA polymerases (RdRp)]. Here, we show that the Semliki Forest virus (SFV) RNA replicase can induce IFN-β independently of viral RNA replication and transcription. The SFV replicase converts host cell RNA into 5′-ppp dsRNA and induces IFN-β through the RIG-I and MDA-5 pathways. Inactivation of the SFV replicase RdRp activity prevents IFN-β induction. These IFN-inducing modified host cell RNAs are abundantly produced during both wild-type SFV and its non-pathogenic mutant infection. Furthermore, in contrast to the wild-type SFV replicase a non-pathogenic mutant replicase triggers increased IFN-β production, which leads to a shutdown of virus replication. These results suggest that host cells can restrict RNA virus replication by detecting the products of unspecific viral replicase RdRp activity.

【 授权许可】

CC BY