title: Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.
abstract: For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection.
authors.affiliation: Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Painter
authors.affiliation: Department of Molecular Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Morrison
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Zoecklein
authors.affiliation: Department of Molecular Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Tommy A
authors.initials: TA
authors.lastname: Rinkoski
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Watzlawik
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Papke
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Warrington
authors.affiliation: Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, United State of America.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Bieber
authors.affiliation: Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Matchett
authors.affiliation: Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Kari L
authors.initials: KL
authors.lastname: Turkowski
authors.affiliation: Department of Molecular Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Poeschla
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005814:Genes, Viral / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010849:Picornaviridae / Q000235:genetics / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology / Q000517:prevention & control
chemical_list: D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase