The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response

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  • Enguita, Francisco J.
    • Other Affiliation: Universidade de Lisboa
  • Leitão, Ana Lúcia
    • Other Affiliation: Universidade NOVA de Lisboa
  • McDonald, J. Tyson
    • Other Affiliation: Georgetown University School of Medicine
  • Zaksas, Viktorija
    • Other Affiliation: The University of Chicago
  • Das, Saswati
    • Other Affiliation: Atal Bihari Vajpayee Institute of Medical Sciences
  • Galeano, Diego
    • Other Affiliation: Universidad Nacional de Asunción
  • Taylor, Deanne
    • Other Affiliation: University of Pennsylvania
  • Wurtele, Eve Syrkin
    • Other Affiliation: Iowa State University
  • Saravia-Butler, Amanda
    • Other Affiliation: Logyx LLC
  • Baylin, Stephen B.
    • Other Affiliation: Johns Hopkins School of Medicine
  • Meller, Robert
    • Other Affiliation: Morehouse School of Medicine
  • Porterfield, D. Marshall
    • Other Affiliation: Purdue University
  • Wallace, Douglas C.
    • Other Affiliation: University of Pennsylvania
  • Schisler, Jonathan C.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Mason, Christopher E.
    • Other Affiliation: Weill Cornell Medicine
  • Beheshti, Afshin
    • Other Affiliation: NASA Ames Research Center
Abstract
  • Rationale: Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. Methods: In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load and analyzed the involvement of lncRNAs in supporting regulatory networks based on their interaction with RNA-binding proteins (RBPs). Results: Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RBPs. This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. Conclusions: We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD).
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Theranostics
Journal volume
  • 12
Journal issue
  • 8
Page start
  • 3946
Page end
  • 3962
Language
  • English
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  • Publisher
ISSN
  • 1838-7640

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