Shiftless inhibits flavivirus replication in vitro and is neuroprotective in a mouse model of Zika virus pathogenesis

Natasha W. Hanners, Katrina B. Mar, Ian N. Boys, Jennifer L. Eitson, Pamela C. De La Cruz-Rivera, R. Blake Richardson, Wenchun Fan, Mary Wight-Carter, John W. Schoggins

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Flaviviruses such as Zika virus and West Nile virus have the potential to cause severe neuropathology if they invade the central nervous system. The type I interferon response is well characterized as contributing to control of flavivirus-induced neuropathogenesis. However, the interferon-stimulated gene (ISG) effectors that confer these neuroprotective effects are less well studied. Here, we used an ISG expression screen to identify Shiftless (SHFL, C19orf66) as a potent inhibitor of diverse positive-stranded RNA viruses, including multiple members of the Flaviviridae (Zika, West Nile, dengue, yellow fever, and hepatitis C viruses). In cultured cells, SHFL functions as a viral RNA-binding protein that inhibits viral replication at a step after primary translation of the incoming genome. The murine ortholog, Shfl, is expressed constitutively in multiple tissues, including the central nervous system. In a mouse model of Zika virus infection, Shfl-/- knockout mice exhibit reduced survival, exacerbated neuropathological outcomes, and increased viral replication in the brain and spinal cord. These studies demonstrate that Shfl is an important antiviral effector that contributes to host protection from Zika virus infection and virus-induced neuropathological disease.

Original languageEnglish (US)
Article numbere2111266118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - Dec 7 2021


  • flaviviruses
  • neurotropic viruses
  • pathophysiology
  • type I interferon

ASJC Scopus subject areas

  • General


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