Disruption of nuclear architecture as a cause of COVID-19 induced anosmia

Zazhytska, Marianna; Kodra, Albana; Hoagland, Daisy A.; Fullard, John F.; Shayya, Hani; Omer, Arina; Firestein, Stuart; Gong, Qizhi; Canoll, Peter D.; Goldman, James E.; Roussos, Panos; tenOever, Benjamin R.; Overdevest, Jonathan B.; Lomvardas, Stavros

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.