MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies.
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. 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.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Ryan A
RA
Langlois
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Randy A
RA
Albrecht
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Brian
B
Kimble
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Troy
T
Sutton
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Jillian S
JS
Shapiro
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Courtney
C
Finch
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Matthew
M
Angel
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Mark A
MA
Chua
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Ana Silvia
AS
Gonzalez-Reiche
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Kemin
K
Xu
Department of Veterinary Medicine, University of Maryland, College Park College Park, MD 20742.
Daniel
D
Perez
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Adolfo
A
García-Sastre
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Benjamin R
BR
tenOever
D000818:Animals; D035843:Biomedical Research / Q000379:methods / Q000592:standards; D001835:Body Weight; D005289:Ferrets; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000821:virology; D012308:Risk Management; D016019:Survival Analysis; D056189:Viral Tropism / Q000235:genetics; D014773:Virology / Q000379:methods / Q000592:standards; D014779:Virus Replication / Q000235:genetics
D035683:MicroRNAs