BACKGROUND: A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. METHODS: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. RESULTS: Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. CONCLUSIONS: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.
BACKGROUND: A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. METHODS: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. RESULTS: Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. CONCLUSIONS: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.
Authors: Gary A Churchill; David C Airey; Hooman Allayee; Joe M Angel; Alan D Attie; Jackson Beatty; William D Beavis; John K Belknap; Beth Bennett; Wade Berrettini; Andre Bleich; Molly Bogue; Karl W Broman; Kari J Buck; Ed Buckler; Margit Burmeister; Elissa J Chesler; James M Cheverud; Steven Clapcote; Melloni N Cook; Roger D Cox; John C Crabbe; Wim E Crusio; Ariel Darvasi; Christian F Deschepper; R W Doerge; Charles R Farber; Jiri Forejt; Daniel Gaile; Steven J Garlow; Hartmut Geiger; Howard Gershenfeld; Terry Gordon; Jing Gu; Weikuan Gu; Gerald de Haan; Nancy L Hayes; Craig Heller; Heinz Himmelbauer; Robert Hitzemann; Kent Hunter; Hui-Chen Hsu; Fuad A Iraqi; Boris Ivandic; Howard J Jacob; Ritsert C Jansen; Karl J Jepsen; Dabney K Johnson; Thomas E Johnson; Gerd Kempermann; Christina Kendziorski; Malak Kotb; R Frank Kooy; Bastien Llamas; Frank Lammert; Jean-Michel Lassalle; Pedro R Lowenstein; Lu Lu; Aldons Lusis; Kenneth F Manly; Ralph Marcucio; Doug Matthews; Juan F Medrano; Darla R Miller; Guy Mittleman; Beverly A Mock; Jeffrey S Mogil; Xavier Montagutelli; Grant Morahan; David G Morris; Richard Mott; Joseph H Nadeau; Hiroki Nagase; Richard S Nowakowski; Bruce F O'Hara; Alexander V Osadchuk; Grier P Page; Beverly Paigen; Kenneth Paigen; Abraham A Palmer; Huei-Ju Pan; Leena Peltonen-Palotie; Jeremy Peirce; Daniel Pomp; Michal Pravenec; Daniel R Prows; Zhonghua Qi; Roger H Reeves; John Roder; Glenn D Rosen; Eric E Schadt; Leonard C Schalkwyk; Ze'ev Seltzer; Kazuhiro Shimomura; Siming Shou; Mikko J Sillanpää; Linda D Siracusa; Hans-Willem Snoeck; Jimmy L Spearow; Karen Svenson; Lisa M Tarantino; David Threadgill; Linda A Toth; William Valdar; Fernando Pardo-Manuel de Villena; Craig Warden; Steve Whatley; Robert W Williams; Tim Wiltshire; Nengjun Yi; Dabao Zhang; Min Zhang; Fei Zou Journal: Nat Genet Date: 2004-11 Impact factor: 38.330
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