Combined agonist–antagonist genome-wide functional screening identifies broadly active antiviral microRNAs

Combined agonist–antagonist genome-wide functional screening identifies broadly active antiviral microRNAs
Diwakar Santhakumara,b, Thorsten Forsterb,c, Nouf N. Laqtoma,b,d, Rennos Fragkoudise, Paul Dickinsonb,c, Cei Abreu-Goodgerf, Sergei A. Manakovf, Nila Roy Choudhurye, Samantha J. Griffithsb, Annaleen Vermeuleng, Anton J. Enrightf, Bernadette Dutiae, Alain Kohle, Peter Ghazalb,c, and Amy H. Bucka,b,1
+ Author Affiliations

aCentre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom;
bDivision of Pathway Medicine and Centre for Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom;
cCentre for Systems Biology at Edinburgh, University of Edinburgh, Edinburgh EH9 3JD, United Kingdom;
dDepartment of Biology, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
eThe Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom;
fEuropean Bioinformatics Institute, Cambridge CB10 1SD, United Kingdom; and
gThermo Fisher Scientific, Dharmacon Products, Lafayette, CO 80026
Communicated by Norman R. Pace, University of Colorado, Boulder, CO, June 28, 2010 (received for review April 26, 2010)

Abstract
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.
http://www.pnas.org/content/early/2010/07/15/1008861107.abstract?sid=7b0bfa72-6ead-436d-be90-ec868b64fbf4

open here to see the original research:
http://www.pnas.org/content/early/2010/07/15/1008861107.full.pdf+html