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© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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.

Jeong et al. report a series of COVID-19 patients with hearing- and balance-related symptoms. The authors show that human and mouse inner ear tissues, as well as human inner ear cells and organoids derived from induced pluripotent stem cells, express SARS-CoV-2 entry factors, and that these in vitro models of the human inner ear are susceptible to SARS-CoV-2 infection

Details

Title
Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction
Author
Jeong, Minjin 1 ; Ocwieja, Karen E. 2 ; Han, Dongjun 1 ; Wackym, P. Ashley 3   VIAFID ORCID Logo  ; Zhang, Yichen 4   VIAFID ORCID Logo  ; Brown, Alyssa 5   VIAFID ORCID Logo  ; Moncada, Cynthia 5 ; Vambutas, Andrea 6   VIAFID ORCID Logo  ; Kanne, Theodore 7 ; Crain, Rachel 8 ; Siegel, Noah 9 ; Leger, Valerie 10 ; Santos, Felipe 9 ; Welling, D. Bradley 9   VIAFID ORCID Logo  ; Gehrke, Lee 11 ; Stankovic, Konstantina M. 1 

 Harvard Medical School, Department of Otolaryngology—Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts Eye and Ear, Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Stanford University School of Medicine, Department of Otolaryngology—Head and Neck Surgery, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
 Harvard Medical School, Department of Pediatrics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Boston Children’s Hospital, Department of Pediatrics, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438); Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Boston, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
 Rutgers Robert Wood Johnson Medical School, Department of Otolaryngology—Head and Neck Surgery, New Brunswick, USA (GRID:grid.430387.b) (ISNI:0000 0004 1936 8796) 
 Harvard-MIT Program in Health Science and Technology, Boston, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
 Massachusetts Eye and Ear, Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003) 
 Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Department of Otolaryngology Head and Neck Surgery, New Hyde Park, USA (GRID:grid.512756.2) (ISNI:0000 0004 0370 4759) 
 ENT and Allergy Associates of South Georgia, Valdosta, USA (GRID:grid.512756.2) 
 Brevard ENT Center, Rockledge, USA (GRID:grid.512756.2) 
 Harvard Medical School, Department of Otolaryngology—Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts Eye and Ear, Eaton Peabody Laboratories and Department of Otolaryngology—Head and Neck Surgery, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003) 
10  Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Boston, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
11  Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Boston, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Harvard-MIT Program in Health Science and Technology, Boston, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Harvard Medical School, Department of Microbiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
Pages
44
Publication year
2021
Publication date
Dec 2021
Publisher
Springer Nature B.V.
e-ISSN
2730664X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2788446176
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.