An anatomical model for SARS-CoV-2 entry into mastoid and middle ear in

COVID-19 patients

Dear editor,

Recently Frazier et al detected SARS-CoV-2 RNA in the PCR based testing of

post-mortem biopsy specimens from the middle ear and mastoid cavity of 2 out of

3 COVID-19 patients1. Detection of SARS-CoV-2 in the deeper parts of ear is a

finding of utmost clinical significance and deserves extensive deliberation.

However, how did SARS-CoV-2 reach these parts of the ear, which are not directly

exposed to the external environment, is intriguing and deserves an anatomical

explanation. In this letter, we suggest an anatomical model which can effectively

explain the route of the viral entry from nose to the middle ear and to the mastoid.

To invade and replicate into a human tissue, SARS-CoV-2 binds to a human cell

surface receptor called angiotensin converting enzyme 2 (ACE-2) through the

receptor binding domain (RBD) present at its spike (S) protein2. For the successful

host cell membrane fusion and infectivity, following ACE-2 binding, cleavage of

the viral spike protein (S) by the proteases like transmembrane serine protease-2

(TMPRSS-2) is essential2. Recent studies showed enriched expression of ACE-2

(and also TMPRSS-2) in the epithelial lining of the upper respiratory tract
including the nose in humans3. Similar evidence has been found for the epithelial

lining of the middle ear and mastoid cavities in a recent mouse study4.

The nasopharynx, from where swab is collected for viral testing in COVID-19, is

anatomically unique in the sense that it presents a common meeting place for the

ear, nose, and mouth cavities5. Middle ear opens into the lateral wall of

nasopharynx through ‘Eustachian tube (ET)’—an osteocartilaginous canal which is

about 36 mm in length5 (Fig. 1). ET has important functions of draining the

mucosal secretions from the middle ear cavity to the throat and maintaining the air

pressure in the middle ear cavity allowing controlled passage of the breathing air

through slit shaped nasopharyngeal opening of the tube5. Middle ear is further

connected to the mastoid cavity through a very short passage called aditus5 (Fig. 1).

ET has a lining of respiratory epithelium, and middle ear and mastoid cavities have

simple squamous secretory epithelium, which may allow them to harbour SARS-

CoV-2, owing to abundant expression of the viral cell entry factors3,4. The

nasopharynx has a mucosal continuity with the middle ear and mastoid cavity

through the ET that presents a convenient route for the spread of the virus to the

deep auricular parts (Fig. 1).

Conflict of Interest

Authors declared ‘no conflict of interest’.

Funding

No substantial funding was received for this work.

Author (s) contributions

All contributed equally.

References

1. Frazier KM, Hooper JE, Mostafa HH, Stewart CM. SARS-CoV-2 Virus

Isolated From the Mastoid and Middle Ear. JAMA Otolaryngol Neck Surg.

Published online 2020. doi:10.1001/jamaoto.2020.1922

2. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry

Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven

Protease Inhibitor. Cell 2020;181(2):271-280.e8.

doi:10.1016/j.cell.2020.02.052

3. Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are

highly expressed in nasal epithelial cells together with innate immune genes.

Nat Med. Published online April 23, 2020:1-7. doi:10.1038/s41591-020-

0868-6

4. Uranaka T, Kashio A, Ueha R, et al. Expression of Ace2, Tmprss2, and Furin

in mouse ear tissue. bioRxiv. Published online June 23,

2020:2020.06.23.164335. doi:10.1101/2020.06.23.164335
5. Bluestone CD and Doyle WJ. Anatomy and physiology of eustachian tube

and middle ear related to otitis media. J Allergy Clin Immunol. 1988;81(5 Pt

2):997-1003. doi:10.1016/0091-6749(88)90168-6

Figure Legend

Figure 1 A model depicting anatomical route for transmucosal spread of SARS-CoV-2

from nasopharynx to middle ear and mastoid cavities. (There is an anatomical continuity

from nasopharynx to middle ear and then to mastoid through eustachian tube (ET). This route is

initially lined by mucosal respiratory (nasopharynx to ET) epithelium and then secretory simple

squamous (middle ear and mastoid) epithelium which express ACE-2 receptors that can bind

SARS-CoV-2, hence presents a transmucosal route of spread for entry of the virus while inhaling

air through the nose.