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COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system

Guilherme Dias De Melo, Françoise Lazarini, Sylvain Levallois, Charlotte Hautefort, Vincent Michel, Florence Larrous, Benjamin Verillaud, Caroline Aparicio, Sebastien Wagner, Gilles Gheusi, Lauriane Kergoat, Etienne Kornobis, Thomas Cokelaer, Rémi Hervochon, Yoann Madec, Emmanuel Roze, Dominique Salmon, Hervé Bourhy, Marc Lecuit, Pierre-Marie Lledo
doi: https://doi.org/10.1101/2020.11.18.388819
Guilherme Dias De Melo
1Lyssavirus Epidemiology and Neuropathology Unit, Institut Pasteur, Paris, France
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Françoise Lazarini
2Perception and Memory Unit, Institut Pasteur and CNRS UMR3571, Paris, France
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Sylvain Levallois
3Biology of Infection Unit, Institut Pasteur, Paris, France; Inserm U1117, Paris, France
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Charlotte Hautefort
4Otolaryngology-head and Neck Surgery Department, Hopital Lariboisiere, Assistance Publique – Hôpitaux de Paris, Inserm U1141, Université de Paris, Paris, France
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Vincent Michel
2Perception and Memory Unit, Institut Pasteur and CNRS UMR3571, Paris, France
5Institut de l’Audition, Institut Pasteur, Paris, France; Inserm U1120, Paris, France
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Florence Larrous
1Lyssavirus Epidemiology and Neuropathology Unit, Institut Pasteur, Paris, France
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Benjamin Verillaud
4Otolaryngology-head and Neck Surgery Department, Hopital Lariboisiere, Assistance Publique – Hôpitaux de Paris, Inserm U1141, Université de Paris, Paris, France
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Caroline Aparicio
6Emergency Department, Hôpital Lariboisière, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France
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Sebastien Wagner
2Perception and Memory Unit, Institut Pasteur and CNRS UMR3571, Paris, France
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Gilles Gheusi
2Perception and Memory Unit, Institut Pasteur and CNRS UMR3571, Paris, France
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Lauriane Kergoat
1Lyssavirus Epidemiology and Neuropathology Unit, Institut Pasteur, Paris, France
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Etienne Kornobis
7Plateforme Technologique Biomics – Centre de Ressources et Recherches Technologiques (C2RT), Institut Pasteur, Paris, France
8Hub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, Paris, France
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Thomas Cokelaer
7Plateforme Technologique Biomics – Centre de Ressources et Recherches Technologiques (C2RT), Institut Pasteur, Paris, France
8Hub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, Paris, France
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Rémi Hervochon
9Otolaryngology-head and Neck Surgery Department, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France
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Yoann Madec
10Emerging Diseases Epidemiology Unit, Institut Pasteur, Paris, France
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Emmanuel Roze
11Sorbonne Université, AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Inserm U1127, CNRS UMR 7225, Institut du Cerveau, Paris, France
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Dominique Salmon
12Infectious Diseases and Immunology Department, Cochin Hotel Dieu Hospital, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France
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Hervé Bourhy
1Lyssavirus Epidemiology and Neuropathology Unit, Institut Pasteur, Paris, France
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Marc Lecuit
3Biology of Infection Unit, Institut Pasteur, Paris, France; Inserm U1117, Paris, France
13Université de Paris, Necker-Enfants Malades University Hospital, Division of Infectious Diseases and Tropical Medicine, Institut Imagine, AP-HP, Paris, France
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Pierre-Marie Lledo
2Perception and Memory Unit, Institut Pasteur and CNRS UMR3571, Paris, France
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  • For correspondence: pmlledo@pasteur.fr
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Abstract

While recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Yet, olfactory and taste dysfunction are rather common in COVID-19, especially in pauci-symptomatic patients which constitutes the most frequent clinical manifestation of the infection. We conducted a virologic, molecular, and cellular study of the olfactory system from COVID-19 patients presenting acute loss of smell, and report evidence that the olfactory epithelium represents a highly significant infection site where multiple cell types, including olfactory sensory neurons, support cells and immune cells, are infected. Viral replication in the olfactory epithelium is associated with local inflammation. Furthermore, we show that SARS-CoV-2 induces acute anosmia and ageusia in golden Syrian hamsters, both lasting as long as the virus remains in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling in COVID-19 patients presenting with persistent loss of smell reveals the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. Viral persistence in the olfactory epithelium therefore provides a potential mechanism for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management and future therapeutic strategies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Corresponding authors.

  • * Conflict of interest: The authors have declared that no conflict of interest exists.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system
Guilherme Dias De Melo, Françoise Lazarini, Sylvain Levallois, Charlotte Hautefort, Vincent Michel, Florence Larrous, Benjamin Verillaud, Caroline Aparicio, Sebastien Wagner, Gilles Gheusi, Lauriane Kergoat, Etienne Kornobis, Thomas Cokelaer, Rémi Hervochon, Yoann Madec, Emmanuel Roze, Dominique Salmon, Hervé Bourhy, Marc Lecuit, Pierre-Marie Lledo
bioRxiv 2020.11.18.388819; doi: https://doi.org/10.1101/2020.11.18.388819
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COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system
Guilherme Dias De Melo, Françoise Lazarini, Sylvain Levallois, Charlotte Hautefort, Vincent Michel, Florence Larrous, Benjamin Verillaud, Caroline Aparicio, Sebastien Wagner, Gilles Gheusi, Lauriane Kergoat, Etienne Kornobis, Thomas Cokelaer, Rémi Hervochon, Yoann Madec, Emmanuel Roze, Dominique Salmon, Hervé Bourhy, Marc Lecuit, Pierre-Marie Lledo
bioRxiv 2020.11.18.388819; doi: https://doi.org/10.1101/2020.11.18.388819

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