Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein.
Alphaviruses are mosquito-borne viruses that cause serious human and animal diseases. Previous studies demonstrated that a determinant within the nsP1/nsP2 cleavage domain of the virulent Sindbis AR86 virus played a key role in regulating adult mouse virulence without adversely affecting viral replication. Additional characterization of this determinant demonstrated that a virus with the attenuating mutation induced more type I IFN production both in vivo and in vitro. Interestingly, this phenotype was not specific to the Sindbis AR86 virus, as a similar mutation in a distantly related alphavirus, Ross River Virus (RRV), also led to enhanced IFN induction. This effect was independent of virus-induced host shutoff, since IRF-3 phosphorylation, which occurs independently of de novo host transcription/translation, was induced more robustly in cells infected with the mutant viruses. Altogether, these results demonstrate that critical determinants within the nsP1/nsP2 cleavage domain play an important role in regulating alphavirus-induced IFN responses.
Cruz
Catherine C
CC
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Suthar
Mehul S
MS
Department of Immunology, University of Washington, Seattle, WA 98195-76504, USA.
Montgomery
Stephanie A
SA
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Shabman
Reed
R
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Simmons
Jason
J
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Johnston
Robert E
RE
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Morrison
Thomas E
TE
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology, The University of Colorado Denver, Aurora, CO 80045.
Heise
Mark T
MT
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: heisem@med.unc.edu.
D018354:Alphavirus Infections / Q000378:metabolism / Q000821:virology; D000818:Animals; D002460:Cell Line; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D007739:L Cells; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D012398:Ross River virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D012845:Sindbis Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D015533:Transcriptional Activation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000378:metabolism / Q000502:physiology*
D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; C104211:nsP1 protein, Sindbis virus; D012313:RNA