In vivo analysis of influenza A mRNA secondary structures identifies critical regulatory motifs

Lisa Marie Simon, Edoardo Morandi, Anna Luganini, Giorgio Gribaudo, Luis Martinez-Sobrido, Douglas H. Turner, Salvatore Oliviero, Danny Incarnato*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)
86 Downloads (Pure)

Abstract

The influenza A virus (IAV) is a continuous health threat to humans as well as animals due to its recurring epidemics and pandemics. The IAV genome is segmented and the eight negative-sense viral RNAs (vRNAs) are transcribed into positive sense complementary RNAs (cRNAs) and viral messenger RNAs (mRNAs) inside infected host cells. A role for the secondary structure of IAV mRNAs has been hypothesized and debated for many years, but knowledge on the structure mRNAs adopt in vivo is currently missing. Here we solve, for the first time, the in vivo secondary structure of IAV mRNAs in living infected cells. We demonstrate that, compared to the in vitro refolded structure, in vivo IAV mRNAs are less structured but exhibit specific locally stable elements. Moreover, we show that the targeted disruption of these high-confidence structured domains results in an extraordinary attenuation of IAV replicative capacity. Collectively, our data provide the first comprehensive map of the in vivo structural landscape of IAV mRNAs, hence providing the means for the development of new RNA-targeted antivirals.

Original languageEnglish
Pages (from-to)7003-7017
Number of pages15
JournalNucleic Acids Research
Volume47
Issue number13
DOIs
Publication statusPublished - 26-Jul-2019

Keywords

  • REVEALS PRINCIPLES
  • BALOXAVIR MARBOXIL
  • VIRAL-RNA
  • VIRUS
  • SHAPE
  • ARCHITECTURE
  • MECHANISMS
  • DISCOVERY
  • SELECTION
  • ALIGNMENT

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