Promotion of Hendra virus replication by microRNA 146a.
Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus. Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-κB-responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro. Blocking miR-146a reduces Hendra virus replication in vitro, suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-κB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro, suggesting that increased NF-κB activity aids Hendra virus replication. Furthermore, overexpression of the IκB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease.
CSIRO Australian Animal Health Laboratory, Geelong, Victoria, Australia.
Cameron R
CR
Stewart
Glenn A
GA
Marsh
Kristie A
KA
Jenkins
Michael P
MP
Gantier
Mark L
ML
Tizard
Deborah
D
Middleton
John W
JW
Lowenthal
Jessica
J
Haining
Leonard
L
Izzard
Tamara J
TJ
Gough
Celine
C
Deffrasnes
John
J
Stambas
Rachel
R
Robinson
Hans G
HG
Heine
Jackie A
JA
Pallister
Adam J
AJ
Foord
Andrew G
AG
Bean
Lin-Fa
LF
Wang
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D045404:Hendra Virus / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000502:physiology*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C404508:RNF11 protein, human