Date Published: October 26, 2016
Publisher: Public Library of Science
Author(s): Chwan Hong Foo, Christina L. Rootes, Karla Cowley, Glenn A. Marsh, Cathryn M. Gould, Celine Deffrasnes, Christopher J. Cowled, Reuben Klein, Sarah J. Riddell, Deborah Middleton, Kaylene J. Simpson, Lin-Fa Wang, Andrew G. D. Bean, Cameron R. Stewart, Christopher F. Basler.
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.
Hendra virus (HeV) and Nipah virus (NiV) are highly pathogenic zoonotic paramyxoviruses belonging to the genus Henipavirus . First isolated in Australia in 1994, HeV disease has caused seven clinically confirmed human cases with four fatalities. NiV initially appeared in Malaysia in 1998–1999, resulting in 105 human fatalities. Since 2001, recurring outbreaks of NiV have been reported in South Asia, resulting in more than 211 deaths and an average case-fatality rate of approximately 75% [2, 3]. Both bat-borne henipaviruses cause severe respiratory illness and encephalitis in humans, however there is a lack of therapies and vaccines. With high fatality rates emphasising the need for effective anti-viral strategies [4–6], a better understanding of henipavirus biology is required.
The development of novel therapeutics for viruses of clinical significance relies on our knowledge of the dynamic interplay between the virus and the human host, and our ability to apply such knowledge to disrupt the viral dependence on host factors. However, progress in our understanding of virus-host interactions of many deadly viruses of significant public health importance (e.g. Ebola, MERS, Nipah virus) is hampered by the high-cost and technical challenges associated with studying these viruses under BSL-3 or BSL-4 conditions. To circumvent these issues, different strategies and approaches have been developed, such as the use of pseudotyped particles  or minigenome assays . These approaches, though of much utility, have their shortcomings; in particular, they cannot fully reproduce the entire life cycle of the virus. Therefore, significant progress still needs to be made towards the development and validation of our capabilities to perform technically-challenging experiments in high biocontainment environments.