Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion

Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are bat-borne viruses that cause fatal disease in humans and a range of other mammalian species. Gaining a deeper understanding of host pathways exploited by henipaviruses for infection may identify targets for new anti-viral thera...

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Bibliographic Details
Published in:PLoS pathogens 2016-10, Vol.12 (10), p.e1005974-e1005974
Main Authors: Foo, Chwan Hong, Rootes, Christina L, Cowley, Karla, Marsh, Glenn A, Gould, Cathryn M, Deffrasnes, Celine, Cowled, Christopher J, Klein, Reuben, Riddell, Sarah J, Middleton, Deborah, Simpson, Kaylene J, Wang, Lin-Fa, Bean, Andrew G D, Stewart, Cameron R
Format: Article
Language:English
Subjects:
Animals
Biology and life sciences
Cancer
Disease
Fatalities
Ferrets
Fluorescent Antibody Technique
Funding
Gene expression
Genome-Wide Association Study
Genomes
Genomics
Health aspects
Hendra virus
Henipavirus
Henipavirus Infections - genetics
Henipaviruses
High-Throughput Nucleotide Sequencing
Horses
Humans
Infections
Laboratories
Medical research
Medicine and Health Sciences
MicroRNA
MicroRNAs
MicroRNAs - genetics
Mustela
Nipah virus
Paramyxoviridae
Protein expression
Real-Time Polymerase Chain Reaction
Research and analysis methods
Virus Internalization
Viruses
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Summary:Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are bat-borne viruses that cause fatal disease in humans and a range of other mammalian species. Gaining a deeper understanding of host pathways exploited by henipaviruses for infection may identify targets for new anti-viral therapies. Here we have performed genome-wide high-throughput agonist and antagonist screens at biosafety level 4 to identify host-encoded microRNAs (miRNAs) impacting henipavirus infection in human cells. Members of the miR-181 and miR-17~93 families strongly promoted Hendra virus infection. miR-181 also promoted Nipah virus infection, but did not affect infection by paramyxoviruses from other genera, indicating specificity in the virus-host interaction. Infection promotion was primarily mediated via the ability of miR-181 to significantly enhance henipavirus-induced membrane fusion. Cell signalling receptors of ephrins, namely EphA5 and EphA7, were identified as novel negative regulators of henipavirus fusion. The expression of these receptors, as well as EphB4, were suppressed by miR-181 overexpression, suggesting that simultaneous inhibition of several Ephs by the miRNA contributes to enhanced infection and fusion. Immune-responsive miR-181 levels was also up-regulated in the biofluids of ferrets and horses infected with Hendra virus, suggesting that the host innate immune response may promote henipavirus spread and exacerbate disease severity. This study is the first genome-wide screen of miRNAs influencing infection by a clinically significant mononegavirus and nominates select miRNAs as targets for future anti-viral therapy development.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005974