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

PLoS Pathogens

Christopher J. Cowled¹  Reuben Klein¹  Sarah J. Riddell¹  Karla Cowley¹  Celine Deffrasnes¹  Chwan Hong Foo¹  Glenn A. Marsh¹  Deborah Middleton¹  Christina L. Rootes¹  Cameron R. Stewart¹  Andrew G. D. Bean²  Lin-Fa Wang³  Kaylene J. Simpson⁴  Cathryn M. Gould⁴ 

[1] CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, Victoria, Australia;Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore;The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia;Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

关键词: MicroRNAs;    Henipavirus;    Respiratory infections;    Cell fusion;    Small interfering RNAs;    HeLa cells;    Ferrets;    RNA synthesis;   

DOI  :  10.1371/journal.ppat.1005974

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY