title: Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome.
abstract: It is not understood how immune inflammation influences the pathogenesis of severe acute respiratory syndrome (SARS). One area of strong controversy is the role of interferon (IFN) responses in the natural history of SARS. The fact that the majority of SARS patients recover after relatively moderate illness suggests that the prevailing notion of deficient type I IFN-mediated immunity, with hypercytokinemia driving a poor clinical course, is oversimplified. We used proteomic and genomic technology to systematically analyze host innate and adaptive immune responses of 40 clinically well-described patients with SARS during discrete phases of illness from the onset of symptoms to discharge or a fatal outcome. A novel signature of high IFN-alpha, IFN-gamma, and IFN-stimulated chemokine levels, plus robust antiviral IFN-stimulated gene (ISG) expression, accompanied early SARS sequelae. As acute illness progressed, SARS patients entered a crisis phase linked to oxygen saturation profiles. The majority of SARS patients resolved IFN responses at crisis and expressed adaptive immune genes. In contrast, patients with poor outcomes showed deviated ISG and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. We contend that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity. The potential for the use of the gene signatures we describe in this study to better assess the immunopathology and clinical management of severe viral infections, such as SARS and avian influenza (H5N1), is therefore worth careful examination.
authors.affiliation: Division of Experimental Therapeutics, University Health Network, MaRS Centre, 3-916 TMDT, 101 College Street, Toronto, Ontario, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Longsi
authors.initials: L
authors.lastname: Ran
authors.forename: Luoling
authors.initials: L
authors.lastname: Xu
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Bermejo-Martin
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Cameron
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Muller
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Gold
authors.forename: Susan E
authors.initials: SE
authors.lastname: Richardson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Poutanen
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Willey
authors.forename: Mark E
authors.initials: ME
authors.lastname: DeVries
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.forename: Charit
authors.initials: C
authors.lastname: Seneviratne
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.forename: Desmond
authors.initials: D
authors.lastname: Persad
authors.forename: Peter
authors.initials: P
authors.lastname: Wilkinson
authors.forename: Larry D
authors.initials: LD
authors.lastname: Greller
authors.forename: Roland
authors.initials: R
authors.lastname: Somogyi
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Marie
authors.initials: M
authors.lastname: Louie
authors.forename: Mark B
authors.initials: MB
authors.lastname: Loeb
authors.forename: James
authors.initials: J
authors.lastname: Brunton
authors.forename: Allison J
authors.initials: AJ
authors.lastname: McGeer
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007372:Interferons / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics* / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D007372:Interferons