Rubella Virus Triggers Type I Interferon Antiviral Response in Cultured Human Neural Cells: Involvement in the Control of Viral Gene Expression and Infectious Progeny Production

The type I interferon (IFN) response is one of the primary defense systems against various pathogens. Although rubella virus (RuV) infection is known to cause dysfunction of various organs and systems, including the central nervous system, little is known about how human neural cells evoke protective immunity against RuV infection, leading to controlling RuV replication. Using cultured human neural cells experimentally infected with RuV RA27/3 strain, we characterized the type I IFN immune response against the virus. RuV infected cultured human neural cell lines and induced IFN-beta production, leading to the activation of signal transducer and activator of transcription 1 (STAT1) and the increased expression of IFN-stimulated genes (ISGs). Melanoma-differentiation-associated gene 5 (MDA5), one of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, is required for the RuV-triggered IFN-beta mRNA induction in U373MG cells. We also showed that upregulation of RuV-triggered ISGs was attenuated by blocking IFN-alpha/beta receptor subunit 2 (IFNAR2) using an IFNAR2-specific neutralizing antibody or by repressing mitochondrial antiviral signaling protein (MAVS) expression using MAVS-targeting short hairpin RNA (shRNA). Furthermore, treating RuV-infected cells with BX-795, a TANK-binding kinase 1 (TBK1)/I kappa B kinase epsilon (IKK epsilon) inhibitor, robustly reduced STAT1 phosphorylation and expression of ISGs, enhancing viral gene expression and infectious virion production. Overall, our findings suggest that the RuV-triggered type I IFN-mediated antiviral response is essential in controlling RuV gene expression and viral replication in human neural cells.

Automated summary

This study reveals that the type I interferon immune response is crucial in controlling rubella virus gene expression and replication in human neural cells. Rubella virus infection induces IFN-beta production and increases the expression of IFN-stimulated genes (ISGs). The induction of IFN-beta mRNA in response to rubella virus requires the involvement of cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor melanoma-differentiation-associated gene 5 (MDA5). Blocking IFN-alpha/beta receptor subunit 2 (IFNAR2) or repressing mitochondrial antiviral signaling protein (MAVS) expression attenuates rubella virus-induced upregulation of ISGs. Moreover, treatment with a TBK1/IKKε inhibitor, BX-795, reduces ISG expression in rubella virus-infected cells.