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

Autor: Alexa N. Roth, Lawrence A. Schriefer, Cassandra E Thompson, Rachel Rodgers, Megan T. Baldridge, Jonathan J. Miner, Yuhao Li, Ebrahim Hassan, Stephanie M. Karst, Forrest C. Walker, Dylan Lawrence, Carla Blum-Johnston, Sanghyun Lee, Vincent R. Graziano, Broc T. McCune, Gowri Kalugotla, Larissa Lushniak, Stefan T. Peterson, Craig B. Wilen, Timothy J. Nice
Rok vydání: 2020
Předmět:
RNA viruses
viruses
ved/biology.organism_classification_rank.species
medicine.disease_cause
Virus Replication
Pathology and Laboratory Medicine
Monocytes
Viral Packaging
Mice
White Blood Cells
Animal Cells
Medicine and Health Sciences
Biology (General)
Pathogen
Caliciviridae Infections
Mutation
Mammalian Genomics
Virulence
Genomics
Viral Persistence and Latency
Capsid
Medical Microbiology
Viral evolution
Viral Pathogens
Viruses
Anatomy
Pathogens
Cellular Types
Research Article
QH301-705.5
Immune Cells
Immunology
Biology
Polymorphism
Single Nucleotide
Microbiology
Virus
Caliciviruses
Viral Evolution
Virology
medicine
Genetics
Animals
Molecular Biology
Microbial Pathogens
Evolutionary Biology
Blood Cells
ved/biology
Norovirus
Organisms
Biology and Life Sciences
Cell Biology
RC581-607
Immunity
Innate
Viral Replication
Organismal Evolution
Gastrointestinal Tract
Viral replication
Animal Genomics
Microbial Evolution
Parasitology
Capsid Proteins
Genetic Fitness
Immunologic diseases. Allergy
Digestive System
Murine norovirus
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 17, Iss 3, p e1009402 (2021)
ISSN: 1553-7374
Popis: 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.
Author summary The evolution of viruses both within a single host and during transmission between hosts often leads to novel characteristics as mutations develop, with increased lethality or transmissibility being particularly concerning potential outcomes. Here, using a novel in vivo experimental evolution strategy with intestinal pathogen murine norovirus (MNoV), we identified a single nucleotide mutation that consistently and exclusively arose when mice lacking interferon signaling, a key aspect of the early innate immune response, were infected intracranially with a nonlethal strain of MNoV. This mutation was both sufficient and necessary for viral virulence, conferring virulence by enhanced infection of immune cells to facilitate systemic spread, representing a shift in the cell types infected by the virus. Conversely, this mutation was also associated with more limited infection in the intestine, suggesting a fitness cost. Our work identifies key immunological constraints on the evolution of virulence and provides specific mechanistic insights into viral pathogenesis.
Databáze: OpenAIRE
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