Combined agonist-antagonist genome-wide functional screening identifies broadly active antiviral microRNAs.
Although the functional parameters of microRNAs (miRNAs) have been explored in some depth, the roles of these molecules in viral infections remain elusive. Here we report a general method for global analysis of miRNA function that compares the significance of both overexpressing and inhibiting each mouse miRNA on the growth properties of different viruses. Our comparative analysis of representatives of all three herpesvirus subfamilies identified host miRNAs with broad anti- and proviral properties which extend to a single-stranded RNA virus. Specifically, we demonstrate the broad antiviral capacity of miR-199a-3p and illustrate that this individual host-encoded miRNA regulates multiple pathways required and/or activated by viruses, including PI3K/AKT and ERK/MAPK signaling, oxidative stress signaling, and prostaglandin synthesis. Global miRNA expression analysis further demonstrated that the miR-199a/miR-214 cluster is down-regulated in both murine and human cytomegalovirus infection and manifests similar antiviral properties in mouse and human cells. Overall, we report a general strategy for examining the contributions of individual host miRNAs in viral infection and provide evidence that these molecules confer broad inhibitory potential against multiple viruses.
Santhakumar
Diwakar
D
Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
Forster
Thorsten
T
Laqtom
Nouf N
NN
Fragkoudis
Rennos
R
Dickinson
Paul
P
Abreu-Goodger
Cei
C
Manakov
Sergei A
SA
Choudhury
Nila Roy
NR
Griffiths
Samantha J
SJ
Vermeulen
Annaleen
A
Enright
Anton J
AJ
Dutia
Bernadette
B
Kohl
Alain
A
Ghazal
Peter
P
Buck
Amy H
AH
D000818:Animals; D000998:Antiviral Agents / Q000032:analysis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D055106:Genome-Wide Association Study / Q000379:methods*; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000032:analysis* / Q000494:pharmacology; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000187:drug effects
D000998:Antiviral Agents; D035683:MicroRNAs