Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction

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.

Abstract

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

Plain language summary

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the novel coronavirus SARS-CoV-2. A growing number of sensory symptoms have been linked to this illness. Here, we describe patients with COVID-19 and new-onset of hearing loss, tinnitus and/or dizziness. To examine the underlying molecular mechanisms of these symptoms, we studied human and mouse inner ear tissue. We also generated some of the first human cellular models of infectious inner ear disease. We show that human and mouse inner ear cells have the molecular machinery to allow SARS-CoV-2 entry. We further show that SARS-CoV-2 can infect specific human inner ear cell types. Our findings suggest that inner ear infection may underlie COVID-19-associated problems with hearing and balance.