SARS-CoV-2 Virus Can Infect the Inner Ear

A new study from MIT and Massachusetts Eye and Ear provides evidence that the SARS-CoV-2 virus can infect cells of the inner ear. Credit: Christine Daniloff, MIT

The prevalence of auditory symptoms in Covid-19 patients is unknown, but an infection of the inner ears may be responsible for hearing and balance problems.

Many Covid-19 patients have reported symptoms affecting the ears, including hearing loss and tinnitus. Dizziness and balance problems may also occur, suggesting that the SARS-CoV-2 virus may infect the inner ear.

A new study from MIT and Massachusetts Eye and Ear provides evidence that the virus can indeed infect cells of the inner ear, including hair cells, which are essential for both hearing and balance. The researchers also found that the infection pattern seen in the tissue of the human inner ear is consistent with the symptoms seen in a study of 10 Covid-19 patients who reported a variety of ear-related symptoms.

The researchers used new cellular models of the human inner ear they developed, as well as hard-to-obtain adult human inner ear tissue for their studies. The limited availability of such tissue has hampered previous investigations into Covid-19 and other viruses that can cause hearing loss.

“Having the models is the first step, and this work now opens up a way to work not only with SARS-CoV-2, but other viruses that affect hearing,” said Lee Gehrke, the Hermann LF von Helmholtz professor at the MIT Institute for Medical Engineering and Science, who co-led the study.

Konstantina Stankovic, former associate professor at Harvard Medical School and former chief of otology and neurotology at Massachusetts Eye and Ear, who is now the Bertarelli Foundation Professor and Chair of the Division of Otolaryngology – Head and Neck Surgery at Stanford University School of Medicine, the co-led study. Minjin Jeong, a former postdoc in Stankovic’s lab at Harvard Medical School, who is now at Stanford Medical School, is the lead author of the paper, which was published October 29, 2021 in Communications Medicine.

Ear Infection Models

Before the Covid-19 pandemic began, Gehrke and Stankovic began collaborating on a project to develop cellular models to study infections of the human inner ear. Viruses such as cytomegalovirus, mumps virus, and hepatitis viruses can all cause deafness, but exactly how they do so is not well understood.

In early 2020, after the SARS-CoV-2 virus emerged, the researchers changed their plans. At Massachusetts Eye and Ear, Stankovic began seeing patients with hearing loss, tinnitus and dizziness, who had tested positive for Covid-19. “It was very unclear at the time whether this was causal or coincidental because hearing loss and tinnitus are so common,” she recalls.

She and Gehrke decided to use the model system they were working on to study the infection of SARS-CoV-2. They created their cellular models by taking human skin cells and converting them into induced pluripotent stem cells. Then they were able to stimulate those cells to differentiate into different types of cells found in the inner ear: hair cells, support cells, nerve fibers and Schwann cells, which isolate neurons.

These cells can be grown in a flat, two-dimensional layer or organized in three-dimensional organoids. In addition, the researchers were able to obtain samples of hard-to-obtain inner ear tissue from patients undergoing surgery for a condition that causes severe vertigo or for a tumor that causes hearing loss and vertigo.

In both the human inner ear samples and the stem cell-derived cellular models, the researchers found that certain types of cells — hair cells and Schwann cells — express the proteins needed for the SARS-CoV-2 virus to enter the cells. These proteins include the ACE2 receptor, which is found on cell surfaces, and two enzymes, called furin and transmembrane protease serine 2, that help the virus fuse with the host cell.

The researchers then showed that the virus can actually infect the inner ear, specifically the hair cells and to a lesser extent Schwann cells. They found that the other cell types in their models were not susceptible to SARS-CoV-2 infection.

The human hair cells the researchers studied were vestibular hair cells, which are involved in sensing head movements and maintaining balance. Cochlear hair cells, which are involved in hearing, are much more difficult to obtain or generate in a cellular model. However, the researchers showed that mouse cochlear hair cells also contain proteins that invade SARS-CoV-2.

viral connection

The infection pattern the researchers found in their tissue samples appears to match those seen in a group of 10 Covid-19 patients who reported ear-related symptoms after their infection. Nine of these patients had tinnitus, six had vertigo and all had mild to profound hearing loss.

Damage to cochlear hair cells, which can cause hearing loss, is usually evaluated by measuring otoacoustic emissions — sounds given off by sensory hair cells when they respond to auditory stimulation. Of the six Covid-19 patients in the study who underwent this test, all had reduced or absent otoacoustic emissions.

While this study strongly suggests that Covid-19 can cause hearing and balance problems, the overall percentage of Covid-19 patients who have had ear-related problems is unknown.

“Initially, this was because routine testing was not readily available to patients diagnosed with Covid, and also, when patients had more life-threatening complications, they didn’t pay much attention to whether their hearing was impaired or whether they had tinnitus. ’ says Stankovic. “We still don’t know what the incidence is, but our findings really call for more attention to audiovestibular symptoms in people exposed to Covid.”

Possible routes for the virus to enter the ears include the Eustachian tube, which connects the nose to the middle ear. The virus may also be able to escape from the nose through small openings around the olfactory nerves, Stankovic says. That would allow it to enter the brain space and infect cranial nerves, including the one that connects to the inner ear.

“This paper provides very compelling evidence that Sars-CoV-2 infects the inner ear and may have a causal relationship to hearing and balance symptoms in a number of patients with Covid-19 infection,” said Yuri Agrawal, ENT professor. head and neck surgery at the Johns Hopkins School of Medicine, who was not involved in the study. “Another exciting advancement for our field is the use of 2D and 3D in vitro organoids to observe Sars-CoV-2 infection of the inner ear. This provides a powerful platform to assess the impact of a number of other exposures, including other infections, toxins and cancers, on the inner ear.”

The researchers now hope to use their human cellular models to test potential treatments for the inner ear infections caused by SARS-CoV-2 and other viruses.

Reference: “Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction” by Minjin Jeong, Karen E. Ocwieja, Dongjun Han, P. Ashley Wackym, Yichen Zhang, Alyssa Brown , Cynthia Moncada , Andrea Vambutas, Theodore Kanne, Rachel Crain, Noah Siegel, Valerie Leger, Felipe Santos, D. Bradley Welling, Lee Gehrke and Konstantina M. Stankovic, October 29, 2021, Communications Medicine.
DOI: 10.1038/s43856-021-00044-w

The research was funded by the National Institutes of Health, the Remondi Foundation, the Nancy Sayles Day Foundation and the Barnes Foundation.