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

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posted on 25.07.2020 by Peter Rogan, Ryan Klesc, Eliseos Mucaki, Ben C. Shirley
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 (H3N1), HIV-1, and dengue viral genomes identifies strong RBP binding sites in viral genomes. Replication and expression of viral sequences are 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 complimented 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, multiorgan system failure and the other symptoms that have been described.

Funding

We acknowledge Compute Canada for a special allocation of computing resources dedicated to COVID-19 research.

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