title: Dual microRNA Screens Reveal That the Immune-Responsive miR-181 Promotes Henipavirus Entry and Cell-Cell Fusion.
abstract: 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.
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Chwan Hong
authors: CH
authors: Foo
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Christina L
authors: CL
authors: Rootes
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Karla
authors: http://orcid.org/0000-0001-9757-2627
authors: K
authors: Cowley
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Glenn A
authors: GA
authors: Marsh
authors: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: Cathryn M
authors: CM
authors: Gould
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Celine
authors: http://orcid.org/0000-0003-3878-4771
authors: C
authors: Deffrasnes
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Christopher J
authors: http://orcid.org/0000-0002-1969-9371
authors: CJ
authors: Cowled
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Reuben
authors: R
authors: Klein
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Sarah J
authors: SJ
authors: Riddell
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Deborah
authors: D
authors: Middleton
authors: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
authors: Kaylene J
authors: KJ
authors: Simpson
authors: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors: Lin-Fa
authors: http://orcid.org/0000-0003-2752-0535
authors: LF
authors: Wang
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Andrew G D
authors: AG
authors: Bean
authors: CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia.
authors: Cameron R
authors: CR
authors: Stewart
mesh_terms: D000818:Animals; D005289:Ferrets; D005455:Fluorescent Antibody Technique; D055106:Genome-Wide Association Study; D045403:Henipavirus; D045464:Henipavirus Infections / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006736:Horses; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D053586:Virus Internalization
chemical_list: C000608460:MIRN-181 microRNA, human; D035683:MicroRNAs