title: Overcoming NS1-mediated immune antagonism involves both interferon-dependent and independent mechanisms.
abstract: To ensure survival, our immune system must overcome the action of pathogen-encoded immune antagonists, such as influenza A nonstructural protein-1 (NS1). NS1 subverts the host interferon (IFN) response at multiple levels and blocks the induction of IFN-β, a critical antiviral cytokine. This immune antagonism can be overcome in some cases. It has been shown that IFN-β is upregulated by 48 h in the lungs of wild-type C57BL/6 mice infected with influenza A. In contrast, it is shown here that IFNB1 continues to be repressed in IFNAR1(-/-) IL28Rα(-/-) mice, which are deficient in Type-I and III IFN signaling, implying induction of IFNB1 depends on effective IFN signaling. Despite the complete lack of IFN signaling in this system, some IFN stimulated genes (ISGs) were induced following infection with a Flu strain lacking NS1. While the expression of these viral stress-inducible genes (VSIGs) was initially repressed following infection with wild-type Flu, many of these genes became upregulated by 48 h postinfection. These results demonstrate the existence of IFN-independent mechanisms that can overcome NS1-mediated immune antagonism of VSIGs.
authors.affiliation: 1 Department of Pathology, Yale School of Medicine , New Haven, Connecticut.
authors.forename: Juilee
authors.initials: J
authors.lastname: Thakar
authors.forename: Sonja
authors.initials: S
authors.lastname: Schmid
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Duke
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
mesh_terms: D000818:Animals; D057131:Immune Evasion; D009980:Influenza A virus / Q000276:immunology*; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: C085820:INS1 protein, influenza virus; C508032:Ifnar1 protein, mouse; D018121:Receptors, Cytokine; D017361:Viral Nonstructural Proteins; C471046:interleukin 28alpha receptor; D053633:Receptor, Interferon alpha-beta; D007372:Interferons