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PreprintCited by 12interferon and immune responsesInfluenza Virus Research StudiesImmune Response and Inflammation

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A two-step mechanism for RIG-I activation by influenza virus mvRNAs

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Pitré, Emmanuelle, Bisht, Karishma, Remick, Kaleigh A., Ghorbani, Amir, Yewdell, Jonathan W., Elshina, Elizaveta, te Velthuis, Aartjan J.W.·2025·Science Advances
DOI 10.1101/2025.01.04.630666PMC PMC12333679

Preprint — published as 10.1126/sciadv.adw8034 · Paper page

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Abstract

Influenza A virus (IAV) non-canonical replication products can be bound by host pathogen sensors, such as retinoic acid-inducible gene I (RIG-I). However, innate immune activation is infrequent in cell culture infection, in particular by adapted strains. Moreover, it is not understood why non-canonical IAV RNAs activate RIG-I in a sequence- or RNA structure-dependent manner. We therefore hypothesized that multiple errors need to occur before influenza virus RNA synthesis activates innate immune signaling. To test this idea, we investigated whether RIG-I activation is stimulated by the non-canonical or aberrant transcription of mini viral RNAs (mvRNA), a <125 nt long RNA that is overexpressed in pandemic and highly pathogenic IAV infections. Using mvRNA sequences identified in tissue culture and ferret infections, we find that mvRNAs can cause non-canonical transcription termination through a truncated 5ʹ polyadenylation signal or a 5ʹ transient RNA structure that interrupts polyadenylation. The resulting capped complementary RNAs (ccRNA) can stimulate the release of a template mvRNA in vitro. Finally, we find that both mvRNA and ccRNA sequences can be bound by RIG-I in cell culture and that blocking mvRNA transcription with baloxavir reduces IFN promoter activity. Overall, our findings indicate that sequential rounds of non-canonical or aberrant viral replication and transcription are needed before mvRNAs trigger innate immune signaling in a sequence-dependent manner.

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Metadata

Authors
Pitré, E., Bisht, K., Remick, K. A., Ghorbani, A., Yewdell, J. W., Elshina, E., & te Velthuis, A. J. W.
Affiliations
  • Princeton University (US)
  • National Institutes of Health (US)
  • Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, 08544 New Jersey, United States
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2025-01-04
Volume
11
Issue
32
Pages
eadw8034-eadw8034
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2025.01.04.630666
PMC
PMC12333679
OpenAlex
W4413055725
Cited by
12
References
1
Citations by year
2026: 11 · 2025: 1
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (206579/Z/17/Z)
  • National Institutes of Health (4dp2ai175474-02)
  • National Institute of General Medical Sciences (T32GM148739)
  • National Institute of Allergy and Infectious Diseases (DP2 AI175474)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
influenza A virus, innate immune signaling, polyadenylation, viral RNA synthesis, RNA-dependent RNA polymerase, antiviral innate immunity
MeSH terms
DEAD Box Protein 58, Animals, Humans, Immunity, Innate, Influenza, Human, Influenza A virus, Receptors, Immunologic, RNA, Viral, Transcription, Genetic, Virus Replication, Signal Transduction

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