A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

Tayaza Fadason; Sreemol Gokuladhas; Evgeniia Golovina; Daniel Ho; Sophie Farrow; Denis Nyaga; Hong Pan; Neerja Karnani; Conroy Wong; Antony Cooper; William Schierding; Justin M. O’Sullivan

Interleukin expression is responsible for irreversible, pathological changes associated with 216 SARS-CoV infection in the lung (e. g. [44] ). Human coronavirus has been shown to fine-tune 217 NF-κB signaling [45] . PIR encodes a non-heme iron binding protein that is a redox switch that 218 modulates the binding of p65 (RelA) to NF-κB responsive promoters [46] . NF-κB regulates 219 multiple immune function aspects, including the production of pro-inflammatory 220 cytokines [47] . Therefore, it is notable that repressor regulatory sequences for PIR sit within 221 the ACE2 gene (Fig 2A) . We postulate that the chromatin modifications that silence ACE2 222 expression upon early stage infection activate the PIR repressor ( Fig 2B) . This reduces 223 responsiveness of NF-κB, and thereby delays the expected and needed anti-viral response. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.14.042002 doi: bioRxiv preprint