The incidence of auditory symptoms in Covid-19 patients is unknown, but infection of the inner ears may be due to hearing and balance problems.
Many Covid-19 patients have reported symptoms affecting the ears, including hearing loss and tinnitus. Dizziness and balance problems can also occur, suggesting that SARS-CoV-2 virus may possibly infect the inner ear.
A new study from WITH and the Massachusetts Eye and Ear provide evidence that the virus can actually infect cells in the inner ear, including hair cells that are critical for both hearing and balance. The researchers also found that the infection pattern seen in human inner ear tissue is consistent with the symptoms seen in a study of 10 Covid-19 patients who reported a range of ear-related symptoms.
The researchers used new cellular models of the human inner ear that they developed, as well as hard-to-reach adult human inner ear tissue for their studies. The limited availability of such tissue has hindered previous studies of Covid-19 and other viruses that can cause hearing loss.
“Having the models is the first step, and this work now opens the way for working with not only SARS-CoV-2, but also other viruses that affect hearing,” said Lee Gehrke, Hermann LF von Helmholtz professor at MIT’s Institute for Medical Engineering and Science, which co-led the study.
Konstantina Stankovic, a former associate professor at Harvard Medical School and former head of otology and neurotology at the Massachusetts Eye and Ear, who is now a Bertarelli Foundation professor and chair of the Department of Otolaryngology – Head and Neck Surgery at Stanford University School of Medicine, was with to lead the study. Minjin Jeong, a former postdoc in Stankovic’s laboratory at Harvard Medical School, now at Stanford Medical School, is the lead author of the paper, published October 29, 2021, in Communication medicine.
Models of ear infection
Before the Covid-19 pandemic began, Gehrke and Stankovic began working together on a project to develop cellular models to study infections in the human inner ear. Viruses like cytomegalovirus, mumps virus and hepatitis virus can all cause deafness, but exactly how they do it is not well understood.
In early 2020, after the SARS-CoV-2 virus appeared, the researchers changed their plans. At the Massachusetts Eye and Ear, Stankovic began seeing patients experiencing hearing loss, tinnitus, and dizziness who tested positive for Covid-19. “It was very unclear at the time whether this was causal or accidental 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 infection with SARS-CoV-2. They created their cellular models by taking human skin cells and transforming them into induced pluripotent stem cells. They were then able to stimulate these cells to differentiate into several 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-reach inner ear tissue from patients who underwent surgery for a disorder that causes severe bouts of dizziness or for a tumor that causes hearing loss and dizziness.
In both samples of the human inner ear 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 SARS-CoV-2 virus to enter in the cells. These proteins include the ACE2 receptor, which is found on cell surfaces, and two enzymes called furin and transmembrane protease serine 2, which help the virus to 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 that the researchers examined were vestibular hair cells, which are involved in feeling the movement of the head and maintaining balance. Cochlear hair cells, which are involved in hearing, are much harder to obtain or generate in a cellular model. However, the researchers showed that cochlear hair cells from mice also have proteins that allow SARS-CoV-2 entry.
The infection pattern that the researchers found in their tissue samples appears to be similar to the symptoms observed in a group of 10 Covid-19 patients who reported ear-related symptoms after their infection. Nine of these patients suffered from tinnitus, six experienced dizziness, and all experienced mild to severe hearing loss.
Damage to cochlear hair cells, which can cause hearing loss, is usually assessed by measuring otoacoustic emissions – sounds emitted by sensory hair cells when they respond to auditory stimulation. Among the six Covid-19 patients in the study who underwent this test, all had reduced or absent otoacoustic emissions.
Although this study strongly suggests that Covid-19 may cause hearing and balance problems, the overall percentage of Covid-19 patients who have experienced ear-related problems is not known.
“Initially, it was because routine tests were not readily available to patients diagnosed with Covid, and also when patients had more life-threatening complications, they were not very aware of whether their hearing was impaired or whether they had tinnitus. ., “says Stankovic. “We still do not know what the incidence is, but our results really require increased awareness of audiovestibular symptoms in people with Covid exposure.”
Possible pathways 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 surrounding the olfactory nerves, Stankovic says. This would allow it to enter the brain space and infect the cranial nerves, including the one that connects to the inner ear.
“This article provides very compelling evidence that Sars-CoV-2 infects the inner ear and may be causally related to hearing and balance symptoms in a number of patients with Covid-19 infection,” said Yuri Agrawal, Professor of Otolaryngology. and neck surgery at the Johns Hopkins School of Medicine, which 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 in the inner ear. This provides a powerful platform to study the effects of a variety of other exposures. , including other infections, toxins and cancers, of the inner ear. “
The researchers now hope to use their human cellular models to test possible treatments for the internal ear infections caused by SARS-CoV-2 and other viruses.
Reference: “Direct SARS-CoV-2 infection in the human inner ear may be underlying 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, Communication 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.