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

Marianna Zazhytska, Albana Kodra, Daisy A. Hoagland, John F. Fullard, Hani Shayya, Arina Omer, Stuart Firestein, Qizhi Gong, Peter D. Canoll, James E. Goldman, Panos Roussos, Benjamin R. tenOever, Jonathan B. Overdevest, Stavros Lomvardas
doi: https://doi.org/10.1101/2021.02.09.430314
Marianna Zazhytska
1Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
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Albana Kodra
1Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Genetics and Development, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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Daisy A. Hoagland
3Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
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John F. Fullard
4Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
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Hani Shayya
1Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Genetics and Development, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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Arina Omer
7Baylor Genetics, 2450 Holcombe Blvd, Houston, TX, 77021, USA
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Stuart Firestein
8Department of Biological Sciences, Columbia University New York, NY, 10027, USA
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Qizhi Gong
9Department of Cell Biology and Human Anatomy, School of Medicine, University of California at Davis, Davis, CA 95616, USA
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Peter D. Canoll
10Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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James E. Goldman
10Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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Panos Roussos
4Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
6Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
11Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
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Benjamin R. tenOever
3Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, NY, 10029, USA
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Jonathan B. Overdevest
12Department of Otolaryngology-Head and Neck Surgery, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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  • For correspondence: sl682@columbia.edu
Stavros Lomvardas
1Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Genetics and Development, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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  • For correspondence: sl682@columbia.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 09, 2021.
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Disruption of nuclear architecture as a cause of COVID-19 induced anosmia
Marianna Zazhytska, Albana Kodra, Daisy A. Hoagland, John F. Fullard, Hani Shayya, Arina Omer, Stuart Firestein, Qizhi Gong, Peter D. Canoll, James E. Goldman, Panos Roussos, Benjamin R. tenOever, Jonathan B. Overdevest, Stavros Lomvardas
bioRxiv 2021.02.09.430314; doi: https://doi.org/10.1101/2021.02.09.430314
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Disruption of nuclear architecture as a cause of COVID-19 induced anosmia
Marianna Zazhytska, Albana Kodra, Daisy A. Hoagland, John F. Fullard, Hani Shayya, Arina Omer, Stuart Firestein, Qizhi Gong, Peter D. Canoll, James E. Goldman, Panos Roussos, Benjamin R. tenOever, Jonathan B. Overdevest, Stavros Lomvardas
bioRxiv 2021.02.09.430314; doi: https://doi.org/10.1101/2021.02.09.430314

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