title: A mouse model for human norovirus.
abstract: Human noroviruses (HuNoVs) cause significant morbidity and mortality worldwide. However, despite substantial efforts, a small-animal model for HuNoV has not been described to date. Since "humanized" mice have been successfully used to study human-tropic pathogens in the past, we challenged BALB/c mice deficient in recombination activation gene (Rag) 1 or 2 and common gamma chain (γc) (Rag-γc) engrafted with human CD34+ hematopoietic stem cells, nonengrafted siblings, and immunocompetent wild-type controls with pooled stool isolates from patients positive for HuNoV. Surprisingly, both humanized and nonhumanized BALB/c Rag-γc-deficient mice supported replication of a GII.4 strain of HuNoV, as indicated by increased viral loads over input. In contrast, immunocompetent wild-type BALB/c mice were not infected. An intraperitoneal route of infection and the BALB/c genetic background were important for facilitating a subclinical HuNoV infection of Rag-γc-deficient mice. Expression of structural and nonstructural proteins was detected in cells with macrophage-like morphology in the spleens and livers of BALB/c Rag-γc-deficient mice, confirming the ability of HuNoV to replicate in a mouse model. In summary, HuNoV replication in BALB/c Rag-γc-deficient mice is dependent on the immune-deficient status of the host but not on the presence of human immune cells and provides the first genetically manipulable small-animal model for studying HuNoV infection.
  
  
  OBJECTIVE
  Human noroviruses are a significant cause of viral gastroenteritis worldwide, resulting in significant morbidity and mortality. Antivirals and vaccines are currently not available, in part due to the inability to study these viruses in a genetically manipulable, small-animal model. Herein, we report the first mouse model for human noroviruses. This model will accelerate our understanding of human norovirus biology and provide a useful resource for evaluating antiviral therapies.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Taube
authors.forename: Abimbola O
authors.initials: AO
authors.lastname: Kolawole
authors.forename: Marina
authors.initials: M
authors.lastname: Höhne
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Handley
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Perry
authors.forename: Larissa B
authors.initials: LB
authors.lastname: Thackray
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Wobus
mesh_terms: D000818:Animals; D017250:Caliciviridae Infections / Q000473:pathology* / Q000821:virology*; D004195:Disease Models, Animal; D005243:Feces / Q000821:virology; D016679:Genome, Viral; D006801:Humans; D008099:Liver / Q000821:virology; D008264:Macrophages / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D029322:Norovirus / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification / Q000472:pathogenicity*; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000821:virology; D019562:Viral Load
chemical_list: D012367:RNA, Viral