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Transcriptomic landscapes of SARS-CoV-2-infected and bystander lung cells reveal a selective upregulation of NF-κB-dependent coding and non-coding proviral transcripts

Abstract : Abstract Detailed knowledge of cellular networks that are modulated by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to understand viral replication and host response. So far, transcriptomic analyses of interactions between SARS-CoV-2 and cells were performed on mixed populations of infected and uninfected cells or using single-cell RNA sequencing, both leading to inaccurate or low-resolution gene expression interpretations. Moreover, they generally focused on annotated messenger RNAs (mRNAs), ignoring other transcripts, such as long non-coding RNAs (lncRNAs) and unannotated RNAs. Here, we performed deep polyA + transcriptome analyses of lung epithelial A549 cells infected with SARS-CoV-2, which were sorted based on the expression of the viral protein spike (S). To increase the sequencing depth and improve the robustness of the analysis, the samples were depleted of viral transcripts. Infection caused a massive reduction in mRNAs and lncRNAs, including transcripts coding for antiviral innate immune proteins, such as interferons (IFNs). This absence of IFN response probably explains the poor transcriptomic response of bystander cells co-cultured with spike positive (S + ) ones. NF-κB and inflammatory response were among the pathways that escaped the global shutoff in S + cells. In agreement with the RNA-seq analysis, inflammatory cytokines, but not IFNs, were produced and secreted by infected cells. Functional investigations revealed the proviral function of the NF-kB subunit p105/p50 and some of its known target genes, including IL32 and IL8, as well as the lncRNA ADIRF-AS1, which we identified as a novel NF-kB target gene. Thus, analyzing the polyA + transcriptome of sorted populations of infected lung cells allowed unprecedented identification of cellular functions that are directly affected by infection and the recovery of coding and non-coding genes that contribute to SARS-CoV-2 replication.
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Preprints, Working Papers, ...
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https://hal-cnrs.archives-ouvertes.fr/hal-03853913
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Submitted on : Tuesday, November 15, 2022 - 3:13:31 PM
Last modification on : Wednesday, November 16, 2022 - 3:56:49 AM

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Ugo Szachnowski, Anvita Bhargava, Maxime Chazal, Dominika Foretek, Sophie-Marie Aicher, et al.. Transcriptomic landscapes of SARS-CoV-2-infected and bystander lung cells reveal a selective upregulation of NF-κB-dependent coding and non-coding proviral transcripts. 2022. ⟨hal-03853913⟩

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