Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia

Marianna Zazhytska, Albana Kodra, Daisy A Hoagland, Justin Frere, John F Fullard, Hani Shayya, Natalie G McArthur, Rasmus Moeller, Skyler Uhl, Arina D Omer, Max E Gottesman, Stuart Firestein, Qizhi Gong, Peter D Canoll, James E Goldman, Panos Roussos, Benjamin R tenOever, Jonathan B Overdevest, Stavros Lomvardas.
Cell. 2022-03-17;185(6):1052-1064.e12.
SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.

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Human and hamster RNAseq, scRNAseq, in situ HiC, supplemental spreadsheets and detailed experimental protocols have been deposited to 4DN portal.
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This study did not generate custom computer code. Any additional information is available from the Lead Contact upon request.