Respiratory syncytial virus (RSV) enhances translation of virus-resembling AU-rich host transcripts.

Background: Viruses strongly rely on the host's translational machinery to produce viral proteins required for replication. However, it is unknown how viruses that do not globally inhibit cap-dependent translation compete with abundant host transcripts for ribosomes. Viral infection often triggers eukaryotic initiator factor 2α (eIF2α) phosphorylation, leading to global 5'-cap-dependent translation inhibition. Respiratory syncytial virus (RSV) encodes mRNAs mimicking 5'-cap structures of host mRNAs and thus inhibition of cap-dependent translation initiation would likely also reduce viral translation.

Methods: RSV-infected HEp-2 and A549 cells were analyzed to determine translation levels using western blotting, indirect immunofluorescent staining and polysome profiling. Transcriptome-wide translation efficiencies of virus-infected cells were compared against mock-infected cells using high-throughput sequencing of poly(A)-tail enriched total mRNA and transcripts associated with heavy polysomes.

Results: We confirmed that RSV limits widespread translation initiation inhibition and unexpectedly found that the fraction of ribosomes within polysomes increases during infection, indicating higher ribosome loading on mRNAs during infection. High-throughput sequencing revealed that virus-resembling, AU-rich host transcripts become more efficient at ribosome recruitment. Using a previously published dataset, we observe similar trends in another negative-sense single-stranded RNA virus, vesicular stomatitis virus (VSV).

Conclusions: These findings revealed that RSV changes the translational landscape by enhancing translation of virus-resembling AU-rich host transcripts rather than inhibiting host translation.