Interferon Signaling-Dependent Contribution of Glycolysis to Rubella Virus Infection

Abstract

Interferons (IFNs) are an essential part of innate immunity and contribute to adaptive immune responses. Here, we employed a loss-of-function analysis with human A549 respiratory epithelial cells with a knockout (KO) of the type I IFN receptor (IFNAR KO), either solely or together with the receptor of type III IFN (IFNAR/IFNLR1 KO). The course of rubella virus (RuV) infection on the IFNAR KO A549 cells was comparable to the control A549. However, on the IFNAR/IFNLR1 KO A549 cells, both genome replication and the synthesis of viral proteins were significantly enhanced. The generation of IFN β during RuV infection was influenced by type III IFN signaling. In contrast to IFNAR KO A549, extracellular IFN β was not detected on IFNAR/IFNLR1 KO A549. The bioenergetic profile of RuV-infected IFNAR/IFNLR1 KO A549 cells generated by extracellular flux analysis revealed a significant increase in glycolysis, whereas mitochondrial respiration was comparable between all three cell types. Moreover, the application of the glucose analogue 2-deoxy-D-glucose (2-DG) significantly increased viral protein synthesis in control A549 cells, while no effect was noted on IFNAR/IFNLR KO A549. In conclusion, we identified a positive signaling circuit of type III IFN signaling on the generation of IFN β during RuV infection and an IFN signaling-dependent contribution of glycolysis to RuV infection. This study on epithelial A549 cells emphasizes the interaction between glycolysis and antiviral IFN signaling and notably, the antiviral activity of type III IFNs against RuV infection, especially in the absence of both type I and III IFN signaling, the RuV replication cycle was enhanced.

Dissecting Rubella Placental Infection in an In Vitro Trophoblast Model

“…RuV infection of BeWo cells was accompanied by a trend towards a reduced mitochondrial respiration. Although not statistically significant, this observation is noteworthy as in epithelial lung carcinoma A549 cells an increase in stressed OCR after injection of respiratory inhibitors was detected [43]. Similar to RuV, ZIKV infection of primary placental cells reduced OCR as indicative for mitochondrial respiration, while glycolysis was not altered [44].…”

Women in the European Virus Bioinformatics Center

“…She obtained a postdoctoral lecture qualification (habilitation) in experimental virology. Currently her research focus includes virus infection-associated metabolic alterations of the RNA viruses rubella virus and Usutu virus and their implication in the associated innate immune response [ 93 , 94 ].…”