SARS-CoV-2 Infection Causes Strong mTORC1 Inhibition and Massive Polysome Collapse

Abstract

Viruses employ distinct strategies to ensure efficient translation of their mRNAs over the host transcripts. SARS-CoV-2 targets host mRNAs and ribosomes to favor its own protein synthesis. However, the modulation of the key signal pathways that control the host protein translation machinery during SARS-CoV-2 infection has not been sufficiently addressed. Here, by employing an early variant and a Delta variant isolate that evolved later in the pandemic demonstrates that SARS-CoV-2 infection results in massive polysome collapse starting from 24 hpi, a hallmark of global translation inhibition. Unexpectedly, eIF2 phosphorylation, commonly targeted by viruses to induce translation arrest, was not involved in the translation arrest, suggesting that SARS-CoV-2 countermeasures by the virus to suppress ISR. eIF4E phosphorylation remained unaltered during the infection, ruling out its involvement in the preferential translation of SARS-CoV-2 transcripts. We find that SARS-CoV-2 infection consistently causes mTORC1 inhibition in a comparable manner across both variants indicating that the virus likely targets mTORC1 pathway to suppress host translation. Interestingly, mTORC1 inhibition by SARS-CoV-2 did not impact the polysomal loading of ribosomal protein transcripts rpS3 and rpL26, suggesting that 5TOP mRNAs are spared from the translation suppression and that ribosomal protein synthesis remains active during the infection. Pharmacological activation of mTORC1 did not significantly impact viral replication, suggesting that mTORC1 inhibition might be selectively restricting the host mRNAs from accessing the translation machinery, facilitating a more robust translation of viral transcripts. This study provides new insights into the molecular interactions by which SARS-CoV-2 variants, despite their different clinical outcomes, converge on a conserved mechanism to manipulate host translation regulatory pathways.