Expression of ACE2, TMPRSS2, and Furin in Mouse Ear Tissue, and the Implications for SARS‐CoV‐2 Infection

Abstract

Objectives/Hypothesis: Intracellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on the interaction between its spike protein with the cellular receptor angiotensin-converting enzyme 2 (ACE2) and depends on Furin-mediated spike protein cleavage and spike protein priming by host cell proteases, including transmembrane protease serine 2 (TMPRSS2). As the expression of ACE2, TMPRSS2, and Furin in the middle and inner ear remain unclear, we analyzed the expression of these proteins in mouse ear tissues.Study Design: Animal Research. Methods: We performed immunohistochemical analysis to examine the distribution of ACE2, TMPRSS2, and Furin in the Eustachian tube, middle ear spaces, and cochlea of mice.Results: ACE2 was present in the nucleus of the epithelium of the middle ear and Eustachian tube, as well as in some nuclei of the hair cells in the organ of Corti, in the stria vascularis, and the spiral ganglion cells. ACE2 was also expressed in the cytoplasm of the stria vascularis. TMPRSS2 was expressed in both the nucleus and cytoplasm in the middle spaces, with the expression being stronger in the nucleus in the mucosal epithelium of the middle ear spaces and Eustachian tube. TMPRSS2 was present in the cytoplasm in the organ of Corti and stria vascularis and in the nucleus and cytoplasm in the spiral ganglion. Furin was expressed in the cytoplasm in the middle ear spaces, Eustachian tube, and cochlea.Conclusions: ACE2, TMPRSS2, and Furin are diffusely present in the Eustachian tube, middle ear spaces, and cochlea, suggesting that these tissues are susceptible to SARS-CoV-2 infection.

Neurotological Manifestations of Patients with COVID-19

“…12 With many other cells such as lung cells, it has recently been shown that middle ear mucosa, Eustachian tube mucosa, stria vascularis, spiral ganglions, neurons and glial cells also express this receptor. 13 In the present study, the reported frequencies of the symptoms and the results demonstrate that in the majority of cases, hearing loss, vertigo and hyperacusis are not isolated symptoms, but accompany taste and/or smell impairments, which supports the theory of neurotrophic mechanism. Furthermore, as the transmission of the virus is mainly through airborne droplets, the first entry points of the eye and upper respiratory tract are the most affected body parts.…”

No lasting impact of Covid-19 on the auditory system: a prospective cohort study

“…One such hypothesis is that they are resulting from direct damage caused by the virus to the organ of Corti, stria vascularis, and/or spiral ganglion. 27,41 For instance, inflammation and oxidative stress are tightly linked to one another, and their activation is simultaneously found in many pathological conditions, including infection with SARS-CoV-2. 42 Inflammation is a natural defense mechanism against pathogens and involves in many autoimmune diseases.…”

Sudden sensorineural hearing loss in a post‐COVID‐19 patient

“… 18 A 53‐year‐old Turkish man with SARS‐CoV‐2 infection, reported complete unilateral SSNHL following COVID‐19 infection 9 and was managed with steroids but the problem persisted after 1 month of steroid treatment. SARS‐CoV‐2 is believed to bind to ACE receptors, 13 which is present on alveolar epithelial cells and endothelial cells, similar ACE receptors are found to be present in epithelial cells of middle ear as well as stria vascularis and spiral ganglion of mice. 13 Apart from this, SARS‐CoV‐2 causes an inflammatory response and causes increase in cytokines such as IL‐1, IL‐6, and TNF alpha, 17 which causes a direct entry into cochlea and causes inflammation leading to cellular stress response causing SNHL and it could be occurring in case of SARS‐CoV‐2 infection.…”