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, immun...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2015-07-01
|
| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00493-15 |
| _version_ | 1818739536325246976 |
|---|---|
| author | Jessica B. Graham Sunil Thomas Jessica Swarts Aimee A. McMillan Martin T. Ferris Mehul S. Suthar Piper M. Treuting Renee Ireton Michael Gale Jennifer M. Lund |
| author_facet | Jessica B. Graham Sunil Thomas Jessica Swarts Aimee A. McMillan Martin T. Ferris Mehul S. Suthar Piper M. Treuting Renee Ireton Michael Gale Jennifer M. Lund |
| author_sort | Jessica B. Graham |
| collection | DOAJ |
| description | 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. IMPORTANCE 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. |
| first_indexed | 2024-12-18T01:26:24Z |
| format | Article |
| id | doaj.art-65d31289859044929ba15da991eaaa1b |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T01:26:24Z |
| publishDate | 2015-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-65d31289859044929ba15da991eaaa1b2022-12-21T21:25:43ZengAmerican Society for MicrobiologymBio2150-75112015-07-016310.1128/mBio.00493-15Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease OutcomesJessica B. Graham0Sunil Thomas1Jessica Swarts2Aimee A. McMillan3Martin T. Ferris4Mehul S. Suthar5Piper M. Treuting6Renee Ireton7Michael Gale8Jennifer M. Lund9Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USADepartment of Immunology, University of Washington School of Medicine, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USADepartment of Immunology, University of Washington School of Medicine, Seattle, Washington, USADepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USADepartment of Pediatrics and Children's Healthcare of Atlanta and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USADepartment of Comparative Medicine, University of Washington, Seattle, Washington, USADepartment of Immunology, University of Washington School of Medicine, Seattle, Washington, USADepartment of Immunology, University of Washington School of Medicine, Seattle, Washington, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USAABSTRACT 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. IMPORTANCE 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.https://journals.asm.org/doi/10.1128/mBio.00493-15 |
| spellingShingle | Jessica B. Graham Sunil Thomas Jessica Swarts Aimee A. McMillan Martin T. Ferris Mehul S. Suthar Piper M. Treuting Renee Ireton Michael Gale Jennifer M. Lund Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes mBio |
| title | Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes |
| title_full | Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes |
| title_fullStr | Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes |
| title_full_unstemmed | Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes |
| title_short | Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes |
| title_sort | genetic diversity in the collaborative cross model recapitulates human west nile virus disease outcomes |
| url | https://journals.asm.org/doi/10.1128/mBio.00493-15 |
| work_keys_str_mv | AT jessicabgraham geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT sunilthomas geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT jessicaswarts geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT aimeeamcmillan geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT martintferris geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT mehulssuthar geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT pipermtreuting geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT reneeireton geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT michaelgale geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes AT jennifermlund geneticdiversityinthecollaborativecrossmodelrecapitulateshumanwestnilevirusdiseaseoutcomes |