Abstract
Antiviral responses are often accompanied by formation of stress granules (SG) in infected cells. However, the triggers for SG formation and the function of SG during infection remain subjects of active investigation. Copy-back viral genomes (cbVGs) are the primary inducers of the Mitochondrial Antiviral Signaling (MAVS) pathway and antiviral immunity during Sendai Virus (SeV) and Respiratory Syncytial virus (RSV) infections. The relationship between cbVGs and SG formation is unknown. Here we show that SG form during infections containing high levels of cbVGs, and not during infections with low levels of cbVGs. Moreover, using RNA fluorescent in situ hybridization to differentiate accumulation of standard viral genomes from cbVGs at a single-cell level during infection, we show that SG form exclusively in cells that accumulate high levels of cbVGs. As expected, virus-induced SG depend on signaling by Protein Kinase R (PKR), however, they form independent of MAVS signaling. Furthermore, inhibition of SG does not affect the induction of antiviral immunity, demonstrating that cbVGs induce antiviral immunity and SG formation through two independent mechanisms. Using live-cell imaging, we show that SG formation is highly dynamic and correlates with a drastic reduction of viral protein expression even in cells infected for several weeks. Together, our data demonstrate that SG are important agents of cbVG-induced interference by reducing viral protein expression independently of the antiviral response and suggest that SG contribute to sustain persistent infections.
One Sentence Summary cbVGs trigger SG independent of the antiviral response during RSV and parainfluenza virus infection leading to a reduction of virus protein expression in acute and persisten infections
Competing Interest Statement
The authors have declared no competing interest.