@article{a4a292784a0840e690cd9fdb70e19305,
title = "Transient RNA structures cause aberrant influenza virus replication and innate immune activation",
abstract = "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.",
author = "Hollie French and Emmanuelle Pitr{\'e} and Oade, {Michael S.} and Elizaveta Elshina and Karishma Bisht and Alannah King and Bauer, {David L.V.} and {te Velthuis}, {Aartjan J.W.}",
note = "Funding Information: We would like to thank J. Rehwinkel for the HEK293 IFN::luc and MAVS-/- cells, F. Vreede for the plasmid expressing the mOrange-tagged PB2 subunit, P. Palese for the A/Brevig Mission/1/18 (H1N1) polymerase subunit expression plasmids, and I. Goodfellow and A. Jahun for the MAVS-FLAG expression plasmid. We thank I. Olendraite, C. Rigby, M. Richard, and M. Funk for discussions. A.J.W.t.V. was supported by joint Wellcome Trust and Royal Society grant 206579/Z/17/Z and the National Institutes of Health grant R21AI147172. E.E. was supported by Engineering and Physical Sciences Research Council scholarship EP/S515322/1. E.P. was supported by a studentship from the Department of Pathology, University of Cambridge. D.L.V.B. was supported by the UK Research and Innovation and the UK Medical Research Council (MR/W005611/1) and by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC011104); the UK Medical Research Council (FC011104); and the Wellcome Trust (FC011104). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",
year = "2022",
month = sep,
doi = "10.1126/sciadv.abp8655",
language = "English (US)",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "36",
}