Comparative profiling of SARS-CoV-2 variant infections reveals diverse impacts on host cell RNA and RNA binding protein distribution and regulation

RNA viruses perturb cellular RNA metabolism to promote viral transcript expression and genome replication. However, the extent of host cell RNA reprogramming and the consequences on RNA binding protein (RBP) expression and localization remain poorly understood. Here, we utilized an integrated set of transcriptomics, proteomics, and high-content imaging approaches to compare the impact of different SARS-CoV-2 variants, including an early viral isolate and later emerging variants of concern (Alpha, Delta and Omicron) on the host cellular RNA and RBP landscapes. While all variants deeply remodelled the host transcriptome in a subcellular compartment-specific manner, we found that Omicron variants express lower levels of viral RNA products compared to earlier variants, while still driving efficient production of viral proteins. The surge in viral RNA expression correlated with altered subcellular RNA biotype distribution, cytoplasmic mRNA exclusion, the selective disruption of the localization of polyA-tail interacting proteins, and the nuclear accumulation of non-coding transcripts such as RN7SL family members and MALAT-1. Unexpectedly, we found many RBPs that exhibiting altered subcellular localization following abiotic innate immune stimulation with poly(I:C) but remained unaltered in cells infected with SARS-CoV-2 variants, revealing a capacity for these viruses to limit the overall impact on the RBP subcellular distribution. Our results further indicate that Omicron infection sustains higher expression levels of proteins components of the signal recognition particle and translation factors, which may enable a more effective production of immune response and viral components. Altogether, this work highlights the deep impact of SARS-CoV-2 infection on host cell RNA regulatory landscape and provides new insights to explain the differential impact of Omicron compared to early SARS-CoV-2 variants. HighlightsO_LISARS-CoV-2 variants drive varying degrees of viral RNA expression in infected Calu-3 cells C_LIO_LIInfection reshapes the host cell RNA landscape in a cell-compartment specific manner C_LIO_LIRN7SL RNA exhibits a strong increase in relative abundance and accumulates in the nucleus of infected cells C_LIO_LISARS-CoV-2 infections impact the localization of polyA-tail binding proteins while blocking the nuclear accumulation of immune response-sensitive RBPs C_LIO_LIOmicron infections are less disruptive to cellular function and sustain the production of translation factors and components of the SRP complex C_LI