title: Porcine reproductive and respiratory syndrome virus inhibits type I interferon signaling by blocking STAT1/STAT2 nuclear translocation.
abstract: Type I interferons (IFNs) IFN-α/β play an important role in innate immunity against viral infections by inducing antiviral responses. Porcine reproductive and respiratory syndrome virus (PRRSV) inhibits the synthesis of type I IFNs. However, whether PRRSV can inhibit IFN signaling is less well understood. In the present study, we found that PRRSV interferes with the IFN signaling pathway. The transcript levels of IFN-stimulated genes ISG15 and ISG56 and protein level of signal transducer and activator of transcription 2 (STAT2) in PRRSV VR2385-infected MARC-145 cells were significantly lower than those in mock-infected cells after IFN-α treatment. IFN-induced phosphorylation of both STAT1 and STAT2 and their heterodimer formation in the PRRSV-infected cells were not affected. However, the majority of the STAT1/STAT2/IRF9 (IFN regulatory factor 9) heterotrimers remained in the cytoplasm of PRRSV-infected cells, which indicates that the nuclear translocation of the heterotrimers was blocked. Overexpression of NSP1β of PRRSV VR2385 inhibited expression of ISG15 and ISG56 and blocked nuclear translocation of STAT1, which suggests that NSP1β might be the viral protein responsible for the inhibition of IFN signaling. PRRSV infection in primary porcine pulmonary alveolar macrophages (PAMs) also inhibited IFN-α-stimulated expression of the ISGs and the STAT2 protein. In contrast, a licensed low-virulence vaccine strain, Ingelvac PRRS modified live virus (MLV), activated expression of IFN-inducible genes, including those of chemokines and antiviral proteins, in PAMs without the addition of external IFN and had no detectable effect on IFN signaling. These findings suggest that PRRSV interferes with the activation and signaling pathway of type I IFNs by blocking ISG factor 3 (ISGF3) nuclear translocation.
authors.affiliation: Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742, USA.
authors.forename: Deendayal
authors.initials: D
authors.lastname: Patel
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Nan
authors.forename: Meiyan
authors.initials: M
authors.lastname: Shen
authors.forename: Krit
authors.initials: K
authors.lastname: Ritthipichai
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Yan-Jin
authors.initials: YJ
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000821:virology; D019316:Porcine respiratory and reproductive syndrome virus / Q000276:immunology / Q000472:pathogenicity*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine
chemical_list: D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor