Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity

Meghan M. Painter, James H. Morrison, Laurie J. Zoecklein, Tommy A. Rinkoski, Jens O. Watzlawik, Louisa M. Papke, Arthur E. Warrington, Allan J. Bieber, William E. Matchett, Kari L. Turkowski, Eric M. Poeschla, Moses Rodriguez

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005311
JournalPLoS Pathogens
Volume11
Issue number12
DOIs
StatePublished - 2015

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RNA Replicase
Innate Immunity
Antiviral Agents
Immune System
Interferons
Emerging Communicable Diseases
Picornaviridae
Gene Regulatory Networks
Adaptive Immunity
Viral Proteins
Catalysis
Autoimmunity
Knockout Mice
Transgenic Mice
Genes
HIV Infections
HIV-1
Up-Regulation
Antigens
Messenger RNA

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Painter, M. M., Morrison, J. H., Zoecklein, L. J., Rinkoski, T. A., Watzlawik, J. O., Papke, L. M., ... Rodriguez, M. (2015). Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. PLoS Pathogens, 11(12), [e1005311]. https://doi.org/10.1371/journal.ppat.1005311

Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. / Painter, Meghan M.; Morrison, James H.; Zoecklein, Laurie J.; Rinkoski, Tommy A.; Watzlawik, Jens O.; Papke, Louisa M.; Warrington, Arthur E.; Bieber, Allan J.; Matchett, William E.; Turkowski, Kari L.; Poeschla, Eric M.; Rodriguez, Moses.

In: PLoS Pathogens, Vol. 11, No. 12, e1005311, 2015.

Research output: Contribution to journalArticle

Painter, MM, Morrison, JH, Zoecklein, LJ, Rinkoski, TA, Watzlawik, JO, Papke, LM, Warrington, AE, Bieber, AJ, Matchett, WE, Turkowski, KL, Poeschla, EM & Rodriguez, M 2015, 'Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity', PLoS Pathogens, vol. 11, no. 12, e1005311. https://doi.org/10.1371/journal.ppat.1005311
Painter MM, Morrison JH, Zoecklein LJ, Rinkoski TA, Watzlawik JO, Papke LM et al. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. PLoS Pathogens. 2015;11(12). e1005311. https://doi.org/10.1371/journal.ppat.1005311
Painter, Meghan M. ; Morrison, James H. ; Zoecklein, Laurie J. ; Rinkoski, Tommy A. ; Watzlawik, Jens O. ; Papke, Louisa M. ; Warrington, Arthur E. ; Bieber, Allan J. ; Matchett, William E. ; Turkowski, Kari L. ; Poeschla, Eric M. ; Rodriguez, Moses. / Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. In: PLoS Pathogens. 2015 ; Vol. 11, No. 12.
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