SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system Does mitochondria collapse upon COVID-19 infection?

Claude Pasquier; Alain Robichon

Our previous published analysis, along with other published works, confirmed that the catalogue of siRNAs is far more complex and extensive than previously thought and that it encompasses larger sets of the transcriptome [26, 28, 29] . A study has shown that an extensive presence of dsRNAs in the Drosophila and C. elegans by high-throughput sequencing involving many categories of RNA included mRNAs and in which miRNA and lncRNA populations appear as a minority component [30] . The extreme severity of COVID-19 regarding the clinical impact in human heath resides in the co-evolution virus/homo sapiens. Amazingly the absence of intra RNA pairing in SARS-CoV-2, the protection of viral genome in de novo synthesized pseudo organelles by host membrane invagination in which the dsRNA during replication by the RNA dependent RNA polymerase is sheltered from degrading host cellular process, make these viruses an evolutionary success to escape and evade RNAi/Dicer/Ago weaponry. Host cells are sensing RNA virus infection by internal receptors. The first pathway of innate immunity receptors is orchestrated by Toll like receptors (TLR3). The second pathway is related to retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Both pathways converge to produce interferons (IFN-α and -β) and p ) and proinflammatory cytokines via NF-kappa B and IRF-3 transcription factors [31] [32] [33] . Upon RNA viral infection, the RNA helicases (RIG-I and MDA-5) binds virus-derived RNAs. The complexes then translocate at the outer mitochondrial membrane to bind with MAVS (mitochondrial antiviral signaling). The bound MAVS acting as scaffold protein recruits downstream effectors to form a "MAVS signalosome" of which the major function resides in drastically inducing the stimulation of the NF-UB and IRF-3 factors [34] . Mitochondria appear to constitute an hub of communication/transmission in the line of cascade of antiviral defense events [34] . Regarding the humans genes targeted by SARS-CoV-2, we observe the presence of USP30 a deubiquitinase specific of mitochondria and FBXO21which is a subunit in an ubiquitin protein ligase complex.