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SARS-CoV-2 utilizes a multipronged strategy to suppress host protein synthesis

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. Here, we use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show SARS-CoV-2 infection leads to a global reduction in translation but that viral transcripts are not preferentially translated. Instead, we reveal that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we show that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.

ORGANISM(S): Severe acute respiratory syndrome coronavirus 2 Homo sapiens

PROVIDER: GSE162323 | GEO | 2021/04/01

REPOSITORIES: GEO

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Project description:The coronavirus disease 2019 (COVID-19) pandemic has affected nearly 700 million and claimed more than 6 million lives. However, the large heterogeneity in disease susceptibility and severity of illness (SOI) remains poorly understood. A growing body of evidence suggests that alveolar epithelial cell type 2 (AT2), which constitute 10-15% of all alveolar cells and are critical for alveolar homeostasis, are the primary targets of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and damage to AT2s may directly contribute to disease severity and poor prognosis in COVID-19 patients. Our in-vitro modeling of SARS-CoV-2 infection, in well-characterized, highly uniform, (r2 at 95% CI = 0.92 ± 0.03), induced pluripotent stem cell (iPSC) derived AT2s from 10 participants of our Mexican American Family Study, showed interindividual variability in infection susceptibility and the post-infection cellular viral load. To understand the underlying mechanism of the AT2’s capacity to regulate SARS-CoV-2 infection and cellular viral load, we performed a systematic characterization of the pre- and post-SARS-CoV-2 challenged AT2 transcriptomes. A total of 1,393 genes were found significantly (Oneway ANOVA FDR corrected p ≤ 0.05; FC abs ≥ 2.0) differentially expressed (DE) between pre- and post-SARS-CoV-2 infection-challenged AT2 and suggest significant upregulation of viral infection-related cellular innate immune response pathways (p-value ≤ 0.05; activation z-score ≥ 3.5), whilst the cholesterol and xenobiotic related metabolic pathways were significantly downregulated (p-value ≤ 0.05; activation z-score ≤ - 3.5). Interestingly, pre-infection expression of 238 DE genes showed a high correlation with the post-infection SARS-CoV-2 viral load (FDR corrected p-value ≤ 0.05, and r2-absolute ≥ 0.57). The 85 genes whose expression was negatively correlated with the viral load showed significant enrichment in viral recognition and cytokine-mediated innate immune GO biological processes (p-value range: 4.65x10-10 to 2.24x10-6). The 153 genes whose expression was positively correlated with the viral load showed significant enrichment in cholesterol homeostasis, extracellular matrix, and MAPK/ERK pathway-related GO biological processes (p-value range: 5.06x10-5 to 6.53x10-4). Overall, our results strongly suggest that AT2s pre-infection innate immunity and metabolic state affects their susceptibility to SARS-CoV-2 infection and viral load.

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SARS-CoV-2 utilizes a multipronged strategy to suppress host protein synthesis

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