A systematic view on influenza induced host shutoff

Abstract

Host shutoff is a common strategy used by viruses to repress cellular mRNA translation and concomitantly allow the efficient translation of viral mRNAs. Here we use RNA-sequencing and ribosome profiling to explore the mechanisms that are being utilized by the Influenza A virus (IAV) to induce host shutoff. We show that viral transcripts are not preferentially translated and instead the decline in cellular protein synthesis is mediated by viral takeover on the mRNA pool. Our measurements also uncover strong variability in the levels of cellular transcripts reduction, revealing that short transcripts are less affected by IAV. Interestingly, these mRNAs that are refractory to IAV infection are enriched in cell maintenance processes such as oxidative phosphorylation. Furthermore, we show that the continuous oxidative phosphorylation activity is important for viral propagation. Our results advance our understanding of IAV-induced shutoff, and suggest a mechanism that facilitates the translation of genes with important housekeeping functions.DOI: http://dx.doi.org/10.7554/eLife.18311.001

Going against the Tide: Selective Cellular Protein Synthesis during Virally Induced Host Shutoff

“…The capacity to generate ATP also increases in VACV-infected cells (24), and elevated RNA translational efficiency that increases protein production likely rapidly boosts energy production. In another route to a similar outcome, IAV-infected cells mainly maintain levels of oxidative phosphorylation proteins by selectively depleting cellular mRNAs, such that those controlling oxidative phosphorylation escape the degradation process (8). Thus, levels of oxidative phosphorylation proteins are maintained over the course of IAV infection, but it is not clear whether the energy production capability is maintained or increased.…”

“…When oxidative phosphorylation is impaired by chemical compounds in VACV-or IAV-infected cells, viral replication is significantly reduced (8,24), demonstrating that oxidative phosphorylation is important in their life cycles. In addition to providing energy for viral replication, increasing or maintaining ATP levels may also prevent viral protein aggregation due to large amount of viral protein production during replication (26).…”

“…Two recent studies, one from our group and one from Stern-Ginossar's group, respectively, employed simultaneous RNA-Seq and Ribo-Seq to provide systematic views of VACV-and IAV-induced host shutoff (8,24). The studies found that, during both viral infections, host shutoff is driven by mRNA depletion (likely triggered by virus-encoded proteins that rapidly degrade host cell mRNAs).…”

“…This suppresses cellular mRNA translation and diverts cellular resources to viral replication (7). Influenza A virus (IAV), an RNA virus, also induces a host shutoff mainly by reducing the abundance of cellular mRNAs (8). Alternatively, poliovirus, a picornavirus, deactivates cellular factors critical for host mRNA translation (9,10), although host mRNA depletion may also play a role.…”

“…Ribosomes are also selectively synthesized in host shutoff induced by both VACV and IAV infections (8,24), at least at certain times during infection. Like the requirement for energy, viral replication requires synthesis of viral proteins, so protection of ribosome function might be expected during a viral shutoff.…”