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

Hollie French, Emmanuelle Pitré, Michael S. Oade, Elizaveta Elshina, Karishma Bisht, Alannah King, View ORCID ProfileDavid L.V. Bauer, View ORCID ProfileAartjan J.W. te Velthuis
doi: https://doi.org/10.1101/2022.01.25.476955
Hollie French
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
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Emmanuelle Pitré
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
2Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
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Michael S. Oade
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
2Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
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Elizaveta Elshina
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
2Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
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Karishma Bisht
2Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
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Alannah King
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
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David L.V. Bauer
3RNA Virus Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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  • ORCID record for David L.V. Bauer
Aartjan J.W. te Velthuis
1University of Cambridge, Department of Pathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
2Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
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  • ORCID record for Aartjan J.W. te Velthuis
  • For correspondence: aj.te.velthuis@princeton.edu
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Abstract

During infection, the influenza A virus RNA polymerase produces both full-length and aberrant RNA molecules, such as defective viral genomes (DVG) and mini viral RNAs (mvRNA). Subsequent innate immune activation involves the binding of host pathogen receptor retinoic acid-inducible gene I (RIG-I) to viral RNAs. However, not all influenza A virus RNAs are strong RIG-I agonists. Here we show that potent innate immune activation by mvRNAs is determined by transient RNA structures, called template loops (t-loop) that stall the viral RNA polymerase. The effect of t-loops depends on the formation of an RNA duplex near the template entry and exit channels of the RNA polymerase, and their effect is enhanced by mutation of the template exit path from the RNA polymerase active site. Overall, these findings provide a mechanism that links aberrant viral replication to the activation of the innate immune response.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 22, 2022.
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Transient RNA structures cause aberrant influenza virus replication and innate immune activation
Hollie French, Emmanuelle Pitré, Michael S. Oade, Elizaveta Elshina, Karishma Bisht, Alannah King, David L.V. Bauer, Aartjan J.W. te Velthuis
bioRxiv 2022.01.25.476955; doi: https://doi.org/10.1101/2022.01.25.476955
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Transient RNA structures cause aberrant influenza virus replication and innate immune activation
Hollie French, Emmanuelle Pitré, Michael S. Oade, Elizaveta Elshina, Karishma Bisht, Alannah King, David L.V. Bauer, Aartjan J.W. te Velthuis
bioRxiv 2022.01.25.476955; doi: https://doi.org/10.1101/2022.01.25.476955

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