Mutations Designed by Ensemble Defect to Misfold Conserved RNA Structures of Influenza A Segments 7 and 8 Affect Splicing and Attenuate Viral Replication in Cell Culture.
Influenza A virus is a significant public health threat, but little is understood about the viral RNA structure and function. Current vaccines and therapeutic options to control influenza A virus infections are mostly protein-centric and of limited effectiveness. Here, we report using an ensemble defect approach to design mutations to misfold regions of conserved mRNA structures in influenza A virus segments 7 and 8. Influenza A mutant viruses inhibit pre-mRNA splicing and attenuate viral replication in cell culture, thus providing evidence for functions of the targeted regions. Targeting these influenza A viral RNA regions provides new possibilities for designing vaccines and therapeutics against this important human respiratory pathogen. The results also demonstrate that the ensemble defect approach is an efficient way to test for function of RNA sequences.
Department of Chemistry, University of Rochester, Rochester, New York, United States of America.
Tian
T
Jiang
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America.
Aitor
A
Nogales
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America.
Steven F
SF
Baker
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America.
Luis
L
Martinez-Sobrido
Department of Chemistry, University of Rochester, Rochester, New York, United States of America.
Douglas H
DH
Turner
D000072283:A549 Cells; D000818:Animals; D018929:Cell Culture Techniques; D017124:Conserved Sequence; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D059370:RNA Folding; D012326:RNA Splicing; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics*; D014779:Virus Replication
D012367:RNA, Viral