Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction
© The Author(s) 2021..
BACKGROUND: COVID-19 is a pandemic respiratory and vascular disease caused by SARS-CoV-2 virus. There is a growing number of sensory deficits associated with COVID-19 and molecular mechanisms underlying these deficits are incompletely understood.
METHODS: We report a series of ten COVID-19 patients with audiovestibular symptoms such as hearing loss, vestibular dysfunction and tinnitus. To investigate the causal relationship between SARS-CoV-2 and audiovestibular dysfunction, we examine human inner ear tissue, human inner ear in vitro cellular models, and mouse inner ear tissue.
RESULTS: We demonstrate that adult human inner ear tissue co-expresses the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. We establish three human induced pluripotent stem cell (hiPSC)-derived in vitro models of the inner ear for infection: two-dimensional otic prosensory cells (OPCs) and Schwann cell precursors (SCPs), and three-dimensional inner ear organoids. Both OPCs and SCPs express ACE2, TMPRSS2, and FURIN, with lower ACE2 and FURIN expression in SCPs. OPCs are permissive to SARS-CoV-2 infection; lower infection rates exist in isogenic SCPs. The inner ear organoids show that hair cells express ACE2 and are targets for SARS-CoV-2.
CONCLUSIONS: Our results provide mechanistic explanations of audiovestibular dysfunction in COVID-19 patients and introduce hiPSC-derived systems for studying infectious human otologic disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1 |
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| Enthalten in: |
Communications medicine - 1(2021), 1 vom: 01., Seite 44 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jeong, Minjin [VerfasserIn] |
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| Anmerkungen: |
Date Revised 07.09.2022 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1038/s43856-021-00044-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Jeong, Minjin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © The Author(s) 2021. | ||
| 520 | |a BACKGROUND: COVID-19 is a pandemic respiratory and vascular disease caused by SARS-CoV-2 virus. There is a growing number of sensory deficits associated with COVID-19 and molecular mechanisms underlying these deficits are incompletely understood | ||
| 520 | |a METHODS: We report a series of ten COVID-19 patients with audiovestibular symptoms such as hearing loss, vestibular dysfunction and tinnitus. To investigate the causal relationship between SARS-CoV-2 and audiovestibular dysfunction, we examine human inner ear tissue, human inner ear in vitro cellular models, and mouse inner ear tissue | ||
| 520 | |a RESULTS: We demonstrate that adult human inner ear tissue co-expresses the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. We establish three human induced pluripotent stem cell (hiPSC)-derived in vitro models of the inner ear for infection: two-dimensional otic prosensory cells (OPCs) and Schwann cell precursors (SCPs), and three-dimensional inner ear organoids. Both OPCs and SCPs express ACE2, TMPRSS2, and FURIN, with lower ACE2 and FURIN expression in SCPs. OPCs are permissive to SARS-CoV-2 infection; lower infection rates exist in isogenic SCPs. The inner ear organoids show that hair cells express ACE2 and are targets for SARS-CoV-2 | ||
| 520 | |a CONCLUSIONS: Our results provide mechanistic explanations of audiovestibular dysfunction in COVID-19 patients and introduce hiPSC-derived systems for studying infectious human otologic disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Stem cells | |
| 650 | 4 | |a Virology | |
| 700 | 1 | |a Ocwieja, Karen E |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Dongjun |e verfasserin |4 aut | |
| 700 | 1 | |a Wackym, P Ashley |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yichen |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Alyssa |e verfasserin |4 aut | |
| 700 | 1 | |a Moncada, Cynthia |e verfasserin |4 aut | |
| 700 | 1 | |a Vambutas, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Kanne, Theodore |e verfasserin |4 aut | |
| 700 | 1 | |a Crain, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Siegel, Noah |e verfasserin |4 aut | |
| 700 | 1 | |a Leger, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Welling, D Bradley |e verfasserin |4 aut | |
| 700 | 1 | |a Gehrke, Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Stankovic, Konstantina M |e verfasserin |4 aut | |
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