title: Genetic diversity in the collaborative cross model recapitulates human West Nile virus disease outcomes.
abstract: West Nile virus (WNV) is an emerging neuroinvasive flavivirus that now causes significant morbidity and mortality worldwide. The innate and adaptive immune responses to WNV infection have been well studied in C57BL/6J inbred mice, but this model lacks the variations in susceptibility, immunity, and outcome to WNV infection that are observed in humans, thus limiting its usefulness to understand the mechanisms of WNV infection and immunity dynamics. To build a model of WNV infection that captures human infection outcomes, we have used the Collaborative Cross (CC) mouse model. We show that this model, which recapitulates the genetic diversity of the human population, demonstrates diversity in susceptibility and outcomes of WNV infection observed in humans. Using multiple F1 crosses of CC mice, we identified a wide range of susceptibilities to infection, as demonstrated through differences in survival, clinical disease score, viral titer, and innate and adaptive immune responses in both peripheral tissues and the central nervous system. Additionally, we examined the Oas1b alleles in the CC mice and confirmed the previous finding that Oas1b plays a role in susceptibility to WNV; however, even within a given Oas1b allele status, we identified a wide range of strain-specific WNV-associated phenotypes. These results confirmed that the CC model is effective for identifying a repertoire of host genes involved in WNV resistance and susceptibility. The CC effectively models a wide range of WNV clinical, virologic, and immune phenotypes, thus overcoming the limitations of the traditional C57BL/6J model, allowing genetic and mechanistic studies of WNV infection and immunity in differently susceptible populations.
  
  
  OBJECTIVE
  Mouse models of West Nile virus infection have revealed important details regarding the innate and adaptive immune responses to this emerging viral infection. However, traditional mouse models lack the genetic diversity present in human populations and therefore limit our ability to study various disease outcomes and immunologic mechanisms subsequent to West Nile virus infection. In this study, we used the Collaborative Cross mouse model to more effectively model the wide range of clinical, virologic, and immune phenotypes present upon West Nile virus infection in humans.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Graham
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Swarts
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Aimee A
authors.initials: AA
authors.lastname: McMillan
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.affiliation: Department of Pediatrics and Children's Healthcare of Atlanta and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Ireton
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA mgale@uw.edu jlund@fhcrc.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: mgale@uw.edu jlund@fhcrc.org.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Lund
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D056704:Adaptive Immunity; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology / Q000821:virology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D060467:Disease Resistance; D004198:Disease Susceptibility; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007113:Immunity, Innate; D051379:Mice / Q000235:genetics; D008815:Mice, Inbred Strains; D010641:Phenotype; D019562:Viral Load; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology / Q000821:virology; D014902:West Nile virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*
chemical_list: D000914:Antibodies, Viral; C509914:Oas1b protein, mouse; D015088:2',5'-Oligoadenylate Synthetase