A proposed molecular mechanism for pathogenesis of severe RNA-viral pulmonary infections.

Autor:	Rogan PK; Biochemistry, University of Western Ontario, London, Ontario, N6A 2C8, Canada.; CytoGnomix Inc, London, Ontario, N5X 3X5, Canada., Mucaki EJ; Biochemistry, University of Western Ontario, London, Ontario, N6A 2C8, Canada., Shirley BC; CytoGnomix Inc, London, Ontario, N5X 3X5, Canada.
Jazyk:	angličtina
Zdroj:	F1000Research [F1000Res] 2020 Aug 07; Vol. 9, pp. 943. Date of Electronic Publication: 2020 Aug 07 (Print Publication: 2020).
DOI:	10.12688/f1000research.25390.2
Abstrakt:	Background: Certain riboviruses can cause severe pulmonary complications leading to death in some infected patients. We propose that DNA damage induced-apoptosis accelerates viral release, triggered by depletion of host RNA binding proteins (RBPs) from nuclear RNA bound to replicating viral sequences. Methods: Information theory-based analysis of interactions between RBPs and individual sequences in the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), Influenza A (H3N2), HIV-1, and Dengue genomes identifies strong RBP binding sites in these viral genomes. Replication and expression of viral sequences is expected to increasingly sequester RBPs - SRSF1 and RNPS1. Ordinarily, RBPs bound to nascent host transcripts prevents their annealing to complementary DNA. Their depletion induces destabilizing R-loops. Chromosomal breakage occurs when an excess of unresolved R-loops collide with incoming replication forks, overwhelming the DNA repair machinery. We estimated stoichiometry of inhibition of RBPs in host nuclear RNA by counting competing binding sites in replicating viral genomes and host RNA. Results: Host RBP binding sites are frequent and conserved among different strains of RNA viral genomes. Similar binding motifs of SRSF1 and RNPS1 explain why DNA damage resulting from SRSF1 depletion is complemented by expression of RNPS1. Clustering of strong RBP binding sites coincides with the distribution of RNA-DNA hybridization sites across the genome. SARS-CoV-2 replication is estimated to require 32.5-41.8 hours to effectively compete for binding of an equal proportion of SRSF1 binding sites in host encoded nuclear RNAs. Significant changes in expression of transcripts encoding DNA repair and apoptotic proteins were found in an analysis of influenza A and Dengue-infected cells in some individuals. Conclusions: R-loop-induced apoptosis indirectly resulting from viral replication could release significant quantities of membrane-associated virions into neighboring alveoli. These could infect adjacent pneumocytes and other tissues, rapidly compromising lung function, causing multiorgan system failure and other described symptoms. Competing Interests: Competing interests: PKR cofounded and BCS is an employee of CytoGnomix Inc. (Copyright: © 2021 Rogan PK et al.)
Databáze:	MEDLINE
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