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

Zazhytska, M.; Kodra, A.; Hoagland, D. A.; Fullard, J.; Shayya, H. J.; Omer, A.; Firestein, S.; Gong, Q.; Canoll, P.; Goldman, J. E.; Roussos, P.; tenOever, B. R.; Overdevest, J. B.; Lomvardas, S.

doi:10.1101/2021.02.09.430314

bioRxiv · 10.1101/2021.02.09.430314

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

Zazhytska, M.·Kodra, A.·Hoagland, D. A.·Fullard, J.·Shayya, H. J.·Omer, A.·Firestein, S.·Gong, Q.·Canoll, P.·Goldman, J. E.·Roussos, P.·tenOever, B. R.·Overdevest, J. B.·Lomvardas, S.

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Abstract

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.

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Zazhytska, M., Kodra, A., Hoagland, D. A., Fullard, J., Shayya, H. J., Omer, A., Firestein, S., Gong, Q., Canoll, P., Goldman, J. E., Roussos, P., tenOever, B. R., Overdevest, J. B., Lomvardas, S.. 2021-02-09. Disruption of nuclear architecture as a cause of COVID-19 induced anosmia. https://doi.org/10.1101/2021.02.09.430314

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