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

In the past weeks we urgently proceeded to a computational search of the SARS-CoV-2 full RNA sequence to explore whether short readings presenting perfect match in reverse complementary strand with RNA candidates from the full human transcriptome might exist. We also examined the possibilities of intra or inter pairing within the full SARS-CoV-2 RNA. Comparative studies were conducted with the SARS-CoV, the MERS-CoV along with two non-virulent coronaviruses (HCoV-229E and HCoV-OC43). The purpose of these searching was guided by the hypothesis that hybrid duplex RNA (one strand from human transcriptome, the other from SARS-CoV-2) could be theoretically formed and consequently might lead to degradation of RNA targets not only in SARS-CoV-2 but more importantly, the other way around, in the human transcriptome. Regarding the length of pairing that qualifies substrates for Dicer, the known biochemistry data documents that a 25-or 30-base pairing length is not necessary for loading onto Dicer and subsequent activation of Ago2 in the RISC complex (although some conflicting reports exist about the structural basis and activity of Dicer) [10] [11] [12] . Dicer can trap dsRNAs pairing over a 19-base length with at least a 2 nt overhang at the 3' end and can then directly transfer the modified/unmodified siRNA to the Ago2 site. This has been demonstrated with fluorometric dsRNA [13] . Some paired 19-mers with a dTdT overhang at the 3' end bind Dicer with high affinity; these sequences are not cleaved by Dicer, are fully transferred to Ago and trigger high-efficiency gene silencing activity [10, 11] . Dicer also binds single RNAs at a specific site with high affinity, the function of which is to accelerate hybridization with a partner from the "soup" of RNA metabolism [14] . The newly in situ-formed dsRNA, which is asymmetric, slides into the endonuclease site for cleavage, and the processed RNAi product is transferred successfully into RISC complex. Authors have shown that the pairing length can be as short as 16 nt, with a several-base overhang at the 3' end to fully bind to Dicer and consecutively activate Ago in the RISC context [10] [11] [12] . In this study, a pairing length for computational searching was set minimally to 20 bases, which leads to 24 mers considering the 2nt overhang in both 3' extremities. Rare candidates were found above 20 bases length considering perfect match.