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1.
J Biol Chem ; 300(7): 107472, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38879005

RESUMEN

African swine fever virus (ASFV) causes severe disease in domestic pigs and wild boars, seriously threatening the development of the global pig industry. Type I interferon (IFN-I) is an important component of innate immunity, inducing the transcription and expression of antiviral cytokines by activating Janus-activated kinase-signal transducer and activator of transcription (STAT). However, the underlying molecular mechanisms by which ASFV antagonizes IFN-I signaling have not been fully elucidated. Therefore, using coimmunoprecipitation, confocal microscopy, and dual luciferase reporter assay methods, we investigated these mechanisms and identified a novel ASFV immunosuppressive protein, pB475L, which interacts with the C-terminal domain of STAT2. Consequently, pB475L inhibited IFN-I signaling by inhibiting STAT1 and STAT2 heterodimerization and nuclear translocation. Furthermore, we constructed an ASFV-B475L7PM mutant strain by homologous recombination, finding that ASFV-B475L7PM attenuated the inhibitory effects on IFN-I signaling compared to ASFV-WT. In summary, this study reveals a new mechanism by which ASFV impairs host innate immunity.


Asunto(s)
Virus de la Fiebre Porcina Africana , Inmunidad Innata , Interferón Tipo I , Factor de Transcripción STAT2 , Transducción de Señal , Proteínas Virales , Animales , Humanos , Fiebre Porcina Africana/inmunología , Fiebre Porcina Africana/virología , Fiebre Porcina Africana/metabolismo , Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/inmunología , Virus de la Fiebre Porcina Africana/genética , Células HEK293 , Evasión Inmune , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT2/metabolismo , Factor de Transcripción STAT2/genética , Porcinos , Proteínas Virales/genética , Proteínas Virales/metabolismo , Proteínas Virales/inmunología
2.
J Virol ; 97(3): e0197722, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-36815839

RESUMEN

African swine fever (ASF) is an acute and severe infectious disease caused by the ASF virus (ASFV). The mortality rate of ASF in pigs can reach 100%, causing huge economic losses to the pig industry. Here, we found that ASFV protein MGF505-7R inhibited the beta interferon (IFN-ß)-mediated Janus-activated kinase-signal transducer and activation of transcription (JAK-STAT) signaling. Our results demonstrate that MGF505-7R inhibited interferon-stimulated gene factor 3 (ISGF3)-mediated IFN-stimulated response element (ISRE) promoter activity. Importantly, we observed that MGF505-7R inhibits ISGF3 heterotrimer formation by interacting with interferon regulatory factor 9 (IRF9) and inhibits the nuclear translocation of ISGF3. Moreover, to demonstrate the role of MGF505-7R in IFN-I signal transduction during ASFV infection, we constructed and evaluated ASFV-ΔMGF505-7R recombinant viruses. ASFV-ΔMGF505-7R restored STAT2 and STAT1 phosphorylation, alleviated the inhibition of ISGF3 nuclear translocation, and showed increased susceptibility to IFN-ß, unlike the parental GZ201801 strain. In conclusion, our study shows that ASFV protein MGF505-7R plays a key role in evading IFN-I-mediated innate immunity, revealing a new mode of evasion for ASFV. IMPORTANCE ASF, caused by ASFV, is currently prevalent in Eurasia, with mortality rates reaching 100% in pigs. At present, there are no safe or effective vaccines against ASFV. In this study, we found that the ASFV protein MGF505-7R hinders IFN-ß signaling by interacting with IRF9 and inhibiting the formation of ISGF3 heterotrimers. Of note, we demonstrated that MGF505-7R plays a role in the immune evasion of ASFV in infected hosts and that recombinant viruses alleviated the effect on type I IFN (IFN-I) signaling and exhibited increased susceptibility to IFN-ß. This study provides a theoretical basis for developing vaccines against ASFV using strains with MGF505-7R gene deletions.


Asunto(s)
Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Interferón Tipo I , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón , Replicación Viral , Animales , Fiebre Porcina Africana/inmunología , Fiebre Porcina Africana/virología , Virus de la Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/inmunología , Inmunidad Innata , Interferón Tipo I/inmunología , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/inmunología , Transducción de Señal , Porcinos , Proteínas Virales/genética , Proteínas Virales/inmunología , Replicación Viral/fisiología , Transporte Activo de Núcleo Celular/genética , Evasión Inmune/genética
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