Transient RNA structures cause aberrant influenza virus replication and innate immune activation.

TitleTransient RNA structures cause aberrant influenza virus replication and innate immune activation.
Publication TypeJournal Article
Year of Publication2022
AuthorsFrench, H, Pitre, E, Oade, MS, Elshina, E, Bisht, K, King, A, Bauer, DLV, Velthuis, AJWTe
JournalSci Adv
Volume8
Issue36
Paginationeabp8655
Date Published2022 Sep 09
ISSN2375-2548
KeywordsCell Line, DEAD Box Protein 58, Humans, Immunity, Innate, Influenza, Human, RNA, Viral, Virus Replication
Abstract

<p>During infection, the influenza A virus RNA polymerase produces both full-length and aberrant RNA molecules, such as defective viral genomes (DVGs) and mini viral RNAs (mvRNAs). Subsequent innate immune activation involves the binding of host pathogen receptor retinoic acid-inducible gene I (RIG-I) to viral RNAs. However, it is not clear what factors determine which influenza A virus RNAs are RIG-I agonists. Here, we provide evidence that RNA structures, called template loops (t-loops), stall the viral RNA polymerase and contribute to innate immune activation by mvRNAs during influenza A virus infection. Impairment of replication by t-loops depends on the formation of an RNA duplex near the template entry and exit channels of the RNA polymerase, and this effect is enhanced by mutation of the template exit path from the RNA polymerase active site. Overall, these findings are suggestive of a mechanism involving polymerase stalling that links aberrant viral replication to the activation of the innate immune response.</p>

DOI10.1126/sciadv.abp8655
Alternate JournalSci Adv
PubMed ID36083899
PubMed Central IDPMC9462681
Grant List / WT_ / Wellcome Trust / United Kingdom
R21 AI147172 / AI / NIAID NIH HHS / United States