RESUMEN
Non-structural NS1 protein of influenza A virus counters host antiviral defences by antagonizing the interferon response. The C-terminal effector domain suppresses the host response and is associated with the pathogenicity of the virus. To better understand the regulatory role of the C-terminal domain, we used reverse genetics system to generate NS1-truncated virus (NS80) and compared the cytokine profiles in the lungs of mice infected with the NS80 mutant and with the control virus A/WSN/33 (WSN). The NS80 virus was attenuated and the viral titer in the lungs was about 25 times lower than viral titer of control A/WSN/33. Mice infected with NS80 virus exhibited more severe clinical symptoms and 2 mice died 6 days post infection. NS80 virus activated retinoic-inducible gene (RIG)-1-like receptor signaling pathway more strongly than control WSN virus and mice infected with NS80 virus exhibited a greater abundance and more diverse cytokine profile. Infection with NS80 virus induced the expression of the following factors: pro-inflammatory cytokines (IL-1α, IL-1ß, TNF-α, IL-16), interferons (IFN-α and IFN-ε), chemokines (CCL2, CCL11, CXCL1, CXCL5, CXCL10, CXCL11 and CXCL13), matrix metallopeptidase 9 (MMP-9), metallopeptidase inhibitor 1 (TIMP-1), macrophage colony-stimulating factor (M-CSF), and vascular cell adhesion protein 1 (VCAM-1). All these cytokines are associated with viral pathogenicity. Our data show that attenuation of the virus should not be directly linked with pathogenicity. Keywords: influenza virus; NS1 protein; cytokines; interferon; pathogenicity.
Asunto(s)
Citocinas/inmunología , Virus de la Influenza A/patogenicidad , Infecciones por Orthomyxoviridae/inmunología , Proteínas no Estructurales Virales/genética , Animales , Ratones , VirulenciaRESUMEN
Type I and type III interferons (IFNs) are induced by viral infection. It was concluded that these IFN species are identical in regulation and biological functions. However, these two systems differ in the tissue expression of their receptors and their transcriptional regulation is fundamentally different as well as cellular signaling pathways that drive expression of each IFN. Here, we have investigated the transcriptional profile of endogenous IFNs after stimulation of cells with exogenous IFNs and subsequent infection of A549 cells with A/chicken/Germany/27 [H7N7] influenza virus. Both type I and type III IFNs exhibit high degree of the cross-induction. Our results show that type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) are better inducers of CXCL10 than type I IFNs. The IFN-ß1a and IFN-λ2 were the most potent IFNs and they highly increased the level of IFN-α, IFN-ß, IFN-λ, and CXCL10 mRNAs. Since type I IFNs up regulated expression of retinoic acid-inducible gene 1 (RIG-1) mRNA, type III IFNs-λ down regulated expression of RIG-1 mRNA in influenza infected cells. IFN-α and IFN-ω induced similar amount of IFN-α, IFN-ß and IFN-λ mRNA but differ in induction of CXCL10 and RIG-1 mRNA.
Asunto(s)
Quimiocina CXCL10/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Interferones/farmacología , Receptores de Ácido Retinoico/metabolismo , Transcripción Genética , Transcriptoma , Adenocarcinoma , Línea Celular Tumoral , Quimiocina CXCL10/genética , Regulación de la Expresión Génica/inmunología , Humanos , Interferones/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Ácido Retinoico/genéticaRESUMEN
No abstract Keywords: murine herpesvirus 68; virus isolates; sequence analysis; restriction fragment length polymorphism.
