Differential Interferon Synthesis and Signaling Between Parainfluenza Virus Acute and Persistently Infected Cells

RNA virus infections can transition from an initial acute infection to a prolonged or persistent infection, in which infected cells survive and continue to produce progeny virus. This presents a major clinical problem as persistently infected (PI) cells extend viral shedding, maintain inflammation, and provide potential sources for new viral variants. The RNA virus, Parainfluenza virus 5 (PIV5), with mutations in the P/V gene region (P/V mutant) is a strong inducer of antiviral responses. Interestingly, over time, there is an emergence of cells that survive as P/V mutant PI cells. Given that changes in innate immune signaling pathways can occur in PI cells, we tested the hypothesis that interferon (IFN) synthesis and signaling of P/V mutant-infected cells would differ between acute-infected and PI cells. In this study, we addressed the activity of IFN against P/V mutant infection. Acute-infected cells showed high IFN synthesis, and induction of interferon stimulated genes (ISGs), whereas PI cells exhibited very little IFN expression or ISG expression. Transcriptomic and biochemical analysis assays revealed decreased IFN synthesis and signaling in PI cells correlated with significant downregulation of transcription factors (RIGI, MDA5, IRF7, STAT1, STAT2, and IRF9), compared to acute-infected cells, where these transcription factors are highly upregulated. The finding of diminished IFN synthesis and signaling after the transition from an initial acute P/V mutant infection to persistent raises the potential to inform therapeutics for PI cells based on modulating IFN pathways.