MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies

• Published in: Nature biotechnology Vol. 31; no. 9; pp. 844 - 847
• Main Authors: Langlois, Ryan A, Albrecht, Randy A, Kimble, Brian, Sutton, Troy, Shapiro, Jillian S, Finch, Courtney, Angel, Matthew, Chua, Mark A, Gonzalez-Reiche, Ana Silvia, Xu, Kemin, Perez, Daniel, García-Sastre, Adolfo, tenOever, Benjamin R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2013; Nature Publishing Group
• Subjects: 631/250/255/2514; 631/326/421; 631/326/596/1578; 631/337/505; Agriculture; Animals; Avian influenza; Avian influenza viruses; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedical research; Biomedical Research - methods; Biomedical Research - standards; Biomedicine; Biosafety; Biotechnology; Body Weight; Control; Disease transmission; Epithelial cells; Ferrets; Genetic aspects; Health aspects; Humans; Influenza; Influenza A virus; Influenza A Virus, H5N1 Subtype - genetics; Influenza A Virus, H5N1 Subtype - pathogenicity; Lectins; letter; Life Sciences; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular biology; Orthomyxoviridae Infections - virology; Pathogens; Physiological aspects; Prevention; Respiratory tract; Risk; Risk factors; Risk Management; Risk reduction; RNA sequencing; Survival Analysis; Viral research; Viral Tropism - genetics; Virology - methods; Virology - standards; Virus replication; Virus Replication - genetics; United States
• DOI: 10.1038/nbt.2666
• EISSN: 1546-1696
• ISSN: 1087-0156

A strategy exploiting species-specific miRNA expression may provide another layer of biosafety in gain-of-function influenza experiments.
Recent gain-of-function studies in influenza A virus H5N1 strains revealed that as few as three-amino-acid changes in the hemagglutinin protein confer the capacity for viral transmission between ferrets
1
,
2
. As transmission between ferrets is considered a surrogate indicator of transmissibility between humans, these studies raised concerns about the risks of gain-of-function influenza A virus research. Here we present an approach to strengthen the biosafety of gain-of-function influenza experiments. We exploit species-specific endogenous small RNAs to restrict influenza A virus tropism. In particular, we found that the microRNA miR-192 was expressed in primary human respiratory tract epithelial cells as well as in mouse lungs but absent from the ferret respiratory tract. Incorporation of miR-192 target sites into influenza A virus did not prevent influenza replication and transmissibility in ferrets, but did attenuate influenza pathogenicity in mice. This molecular biocontainment approach should be applicable beyond influenza A virus to minimize the risk of experiments involving other pathogenic viruses.