Deciphering the miR-29c-3p / TET3 regulatory axis within the SARS-CoV-2-infected midbrain

Long COVID is increasingly associated with persistent neurological symptoms. Bioinformatic analysis identified multiple predicted miR-29c-3p binding sites in the 3'-UTR of Ten-Eleven-Translocation 3 (TET3). Luciferase reporter assays demonstrated that the miR-29c-3p is likely to bind an 8 base pair (bp) sequence within the 3'-UTR of TET3, supporting TET3 as a direct regulatory target. In vivo, an inverse relationship between miR-29c-3p and TET3 expression was observed in virus-positive midbrains from K18-hACE2 mice, while virus-negative and mock-infected midbrains showed no significant changes. The observation that only virus-positive brains showed decreased miR-29c-3p supports an alternative hypothesis that low base levels of miR-29c-3p expression may predispose the brain to viral neuro-invasion. Overall, miR-29c-3p > TET3 signaling emerges as a potential regulator of SARS-CoV-2-induced neurological consequences that warrants further investigation.