Severe acute respiratory syndrome coronavirus 2 may exploit human transcription factors involved in retinoic acid and interferon-mediated response: a hypothesis supported by an in silico analysis

Abstract

\n The SARS-CoV-2 causing acute respiratory disease COVID-19 is considered a worldwide emergency. Since recently it has been found that SARS-coronavirus are dependent on the host transcriptional factors (TF) to express the viral genes, efforts are required to understand the molecular interplay between virus and host response.\n By bioinformatic analysis, we investigated human TF that can bind the SARS-CoV-2 sequence and can be involved in viral transcription. In particular, we analyzed the key role of the TF involved in interferon response.\n We found that several TF could be induced by the interferon antiviral response, specifically some induced by IFN-stimulated gene factor 3 (ISGF3) and by un-phosphorylated ISGF3, that were found to promote the transcription of several viral open reading frame. Moreover, we found 22 TF binding sites that are present only in the sequence of virus infecting humans and not in Bat coronavirus RaTG13.\n The 22 TF are involved in the IFN, the retinoic acid signaling and the regulation of transcription by RNA polymerase II, thus facilitating its own replication cycle. This mechanism, by competition, may steal the human TF involved in these processes, explaining SARS-CoV-2 disruption of the IFN-I signalling in host cells and the mechanism of the SARS retinoic acid depletion syndrome leading to the cytokine storm.\n We identified also three TF binding sites present exclusively in the Brazilian SARS-CoV-2 P.1 variant that may explain the higher severity of the respiratory syndrome in this virus variant.\n These data shed light on SARS-CoV2 dependence from the host transcription machinery associated to interferon response and strengthen our knowledge about the transcription and replicative activity of the virus and could pave the way for new targets drug design and therapeutic approaches.\n