Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid

Forrest C. Walker, Ebrahim Hassan, Stefan T. Peterson, Rachel Rodgers, Lawrence A. Schriefer, Cassandra E. Thompson, Yuhao Li, Gowri Kalugotla, Carla Blum-Johnston, Dylan Lawrence, Broc T. McCune, Vincent R. Graziano, Larissa Lushniak, Sanghyun Lee, Alexa N. Roth, Stephanie M. Karst, Timothy J. Nice, Jonathan J. Miner, Craig B. Wilen, Megan T. Baldridge

Research output: Contribution to journalArticlepeer-review

Abstract

Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and increased extraintestinal dissemination of virus. Interestingly, the trade-off for this mutation was reduced fitness in an IFN-competent host, in which CR6 bearing F514I exhibited decreased intestinal replication and shedding. In an immunodeficient context, a spontaneous amino acid change can thus convert a relatively avirulent viral strain into a lethal pathogen.

Original languageEnglish (US)
Article number1009402
JournalPLoS pathogens
Volume17
Issue number3
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

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

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