TY - JOUR
T1 - Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid
AU - Walker, Forrest C.
AU - Hassan, Ebrahim
AU - Peterson, Stefan T.
AU - Rodgers, Rachel
AU - Schriefer, Lawrence A.
AU - Thompson, Cassandra E.
AU - Li, Yuhao
AU - Kalugotla, Gowri
AU - Blum-Johnston, Carla
AU - Lawrence, Dylan
AU - McCune, Broc T.
AU - Graziano, Vincent R.
AU - Lushniak, Larissa
AU - Lee, Sanghyun
AU - Roth, Alexa N.
AU - Karst, Stephanie M.
AU - Nice, Timothy J.
AU - Miner, Jonathan J.
AU - Wilen, Craig B.
AU - Baldridge, Megan T.
N1 - Publisher Copyright:
© 2021 Public Library of Science. All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103074801&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1009402
DO - 10.1371/journal.ppat.1009402
M3 - Article
C2 - 33705489
AN - SCOPUS:85103074801
SN - 1553-7366
VL - 17
JO - PLoS pathogens
JF - PLoS pathogens
IS - 3
M1 - 1009402
ER -