title: Lack of innate interferon responses during SARS coronavirus infection in a vaccination and reinfection ferret model.
abstract: In terms of its highly pathogenic nature, there remains a significant need to further define the immune pathology of SARS-coronavirus (SARS-CoV) infection, as well as identify correlates of immunity to help develop vaccines for severe coronaviral infections. Here we use a SARS-CoV infection-reinfection ferret model and a functional genomics approach to gain insight into SARS immunopathogenesis and to identify correlates of immune protection during SARS-CoV-challenge in ferrets previously infected with SARS-CoV or immunized with a SARS virus vaccine. We identified gene expression signatures in the lungs of ferrets associated with primary immune responses to SARS-CoV infection and in ferrets that received an identical second inoculum. Acute SARS-CoV infection prompted coordinated innate immune responses that were dominated by antiviral IFN response gene (IRG) expression. Reinfected ferrets, however, lacked the integrated expression of IRGs that was prevalent during acute infection. The expression of specific IRGs was also absent upon challenge in ferrets immunized with an inactivated, Al(OH)(3)-adjuvanted whole virus SARS vaccine candidate that protected them against SARS-CoV infection in the lungs. Lack of IFN-mediated immune enhancement in infected ferrets that were previously inoculated with, or vaccinated against, SARS-CoV revealed 9 IRG correlates of protective immunity. This data provides insight into the molecular pathogenesis of SARS-CoV and SARS-like-CoV infections and is an important resource for the development of CoV antiviral therapeutics and vaccines.
authors.affiliation: Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Kelvin
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Leon
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Cameron
authors.forename: Longsi
authors.initials: L
authors.lastname: Ran
authors.forename: Luoling
authors.initials: L
authors.lastname: Xu
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Chu
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.forename: Qianjun
authors.initials: Q
authors.lastname: Li
authors.forename: Austin
authors.initials: A
authors.lastname: Anderson
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Couch
authors.forename: Stephane G
authors.initials: SG
authors.lastname: Paquette
authors.forename: Ndingsa G
authors.initials: NG
authors.lastname: Fomukong
authors.forename: Otfried
authors.initials: O
authors.lastname: Kistner
authors.forename: Manfred
authors.initials: M
authors.lastname: Lauchart
authors.forename: Thomas
authors.initials: T
authors.lastname: Rowe
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.forename: Colleen B
authors.initials: CB
authors.lastname: Jonsson
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002522:Chlorocebus aethiops; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D005289:Ferrets; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000821:virology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology* / Q000502:physiology; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D059467:Transcriptome; D014611:Vaccination; D014709:Vero Cells; D019562:Viral Load; D014765:Viral Vaccines / Q000008:administration & dosage
chemical_list: D000914:Antibodies, Viral; D015850:Interleukin-6; D014765:Viral Vaccines; D003165:Complement System Proteins; D007372:Interferons