title: Uncoupling of the dynamics of host-pathogen interaction uncovers new mechanisms of viral interferon antagonism at the single-cell level.
abstract: Antiviral defence in mammals is mediated through type-I interferons (IFNs). Viruses antagonise this process through expression of IFN antagonist proteins (IAPs). Understanding and modelling of viral escape mechanisms and the dynamics of IAP action has the potential to facilitate the development of specific and safe drugs. Here, we describe the dynamics of interference by selected viral IAPs, NS1 from Influenza A virus and NS3/4A from Hepatitis C virus. We used Tet-inducible IAP gene expression to uncouple this process from virus-driven dynamics. Stochastic activation of the IFN-β gene required the use of single-cell live imaging to define the efficacy of the inhibitors during the virus-induced signalling processes. We found significant correlation between the onset of IAP expression and halted IFN-β expression in cells where IFN-β induction had already occurred. These data indicate that IAPs not only prevent antiviral signalling prior to IFN-β induction, but can also stop the antiviral response even after it has been activated. We found reduced NF-κB activation to be the underlying mechanism by which activated IFN expression can be blocked. This work demonstrates a new mechanism by which viruses can antagonise the IFN response.
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany ulfert.rand@manchester.ac.uk.
authors.forename: Ulfert
authors.initials: U
authors.lastname: Rand
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Upneet
authors.initials: U
authors.lastname: Hillebrand
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sievers
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Willenberg
authors.affiliation: Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
authors.affiliation: Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany dagmar.wirth@helmholtz-hzi.de.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wirth
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D054884:Host-Pathogen Interactions; D016899:Interferon-beta / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D057054:Molecular Imaging; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D059010:Single-Cell Analysis; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D016899:Interferon-beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C085820:INS1 protein, influenza virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus