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bioRxiv · 10.1101/2023.04.12.536671

SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes

Lüscher Dias, T.·Mamede Costa Andrade da Conceicao, I.·Toledo, N. E.·Queiroz, L. R.·de Castro, I. M. S.·Polidoro, R. B.·Del-Bem, L.-E.·Nakaya, H.·Franco, G. R.
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Abstract

Splicing is a highly conserved, intricate mechanism intimately linked to transcription elongation, serving as a pivotal regulator of gene expression. Alternative splicing may generate specific transcripts incapable of undergoing translation into proteins, designated as unproductive. A plethora of respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), strategically manipulate the hosts splicing machinery to circumvent antiviral responses. During the infection, SARS-CoV-2 effectively suppresses interferon (IFN) expression, leading to B cell and CD8+ T cell leukopenia, while simultaneously increasing the presence of macrophages and neutrophils in patients with severe COVID-19. In this study, we integrated publicly available omics datasets to systematically analyze transcripts at the isoform level and delineate the nascent-peptide translatome landscapes of SARS-CoV-2-infected human cells. Our findings reveal a hitherto uncharacterized mechanism whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling genes, interferon-stimulated genes (ISGs), class I MHC genes, and splicing machinery genes, including IRF7, OAS3, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6, CXCL8, and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs a previously unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.

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Lüscher Dias, T., Mamede Costa Andrade da Conceicao, I., Toledo, N. E., Queiroz, L. R., de Castro, I. M. S., Polidoro, R. B., Del-Bem, L.-E., Nakaya, H., Franco, G. R.. 2023-04-13. SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes. https://doi.org/10.1101/2023.04.12.536671

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