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Cited by 200SARS-CoV-2 and COVID-19 ResearchDental Research and COVID-19Dermatological and COVID-19 studies

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Existence of SARS-CoV-2 Entry Molecules in the Oral Cavity

Open access
Sakaguchi, Wakako, Kubota, Nobuhisa, Shimizu, Tomoko, Saruta, Juri, Fuchida, Shinya, Kawata, Akira, Yamamoto, Yuko, Sugimoto, Masahiro, Yakeishi, Mayumi, Tsukinoki, Keiichi·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21176000PMC PMC7503451
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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and furin, which promote entry of the virus into the host cell, have been identified as determinants of SARS-CoV-2 infection. Dorsal tongue and gingiva, saliva, and tongue coating samples were examined to determine the presence of these molecules in the oral cavity. Immunohistochemical analyses showed that ACE2 was expressed in the stratified squamous epithelium of the dorsal tongue and gingiva. TMPRSS2 was strongly expressed in stratified squamous epithelium in the keratinized surface layer and detected in the saliva and tongue coating samples via Western blot. Furin was localized mainly in the lower layer of stratified squamous epithelium and detected in the saliva but not tongue coating. ACE2, TMPRSS2, and furin mRNA expression was observed in taste bud-derived cultured cells, which was similar to the immunofluorescence observations. These data showed that essential molecules for SARS-CoV-2 infection were abundant in the oral cavity. However, the database analysis showed that saliva also contains many protease inhibitors. Therefore, although the oral cavity may be the entry route for SARS-CoV-2, other factors including protease inhibitors in the saliva that inhibit viral entry should be considered.

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Figures

Figure 1 ACE2: Tongue epithelium staining largely in the spinous and basal cell layers (A). The upper layer of the tongue epithelium shows bacteria and strong positive staining within cells (B). Furin: Tongue epithelium showing consistent staining in the spinous and basal cell layers (C). TMPRSS2: Tongue epithelium showing positive staining (D). The upper layer of the tongue epithelium shows bacteria and strong positive staining within cells (E). N-EL: No immunostaining signals (F). The arrows indicate a strong immunochemical positive signal. Scale bar = 50 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; N-EL, neutrophil-elastase.
Figure 1 ACE2: Tongue epithelium staining largely in the spinous and basal cell layers (A). The upper layer of the tongue epithelium shows bacteria and strong positive staining within cells (B). Furin: Tongue epithelium showing consistent staining in the spinous and basal cell layers (C). TMPRSS2: Tongue epithelium showing positive staining (D). The upper layer of the tongue epithelium shows bacteria and strong positive staining within cells (E). N-EL: No immunostaining signals (F). The arrows indicate a strong immunochemical positive signal. Scale bar = 50 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; N-EL, neutrophil-elastase.CC BY · PubMed Central
Figure 2 The fungiform papilla of the tongue epithelium. Immunohistochemical staining of ACE2 (A), TMPRSS2 (B), and furin (C) in the tongue epithelium, including the taste buds. High magnification image showing ACE2-positive taste cells in the inset. The arrows indicate the taste bud cells. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.
Figure 2 The fungiform papilla of the tongue epithelium. Immunohistochemical staining of ACE2 (A), TMPRSS2 (B), and furin (C) in the tongue epithelium, including the taste buds. High magnification image showing ACE2-positive taste cells in the inset. The arrows indicate the taste bud cells. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.CC BY · PubMed Central
Figure 3 The gingival tissues, including the sulcus epithelium. Immunohistochemical expression of ACE2 (A), TMPRSS2 (B), and furin (C). No N-EL staining was detected in the gingival squamous epithelium (D). High magnification images showing ACE2, TMPRSS2, and furin-positive cells in the gingival squamous epithelium and an N-EL-positive signal in neutrophils. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; N-EL, neutrophil-elastase.
Figure 3 The gingival tissues, including the sulcus epithelium. Immunohistochemical expression of ACE2 (A), TMPRSS2 (B), and furin (C). No N-EL staining was detected in the gingival squamous epithelium (D). High magnification images showing ACE2, TMPRSS2, and furin-positive cells in the gingival squamous epithelium and an N-EL-positive signal in neutrophils. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; N-EL, neutrophil-elastase.CC BY · PubMed Central
Figure 4 The submandibular gland. Immunohistochemical expression of ACE2 (A), TMPRSS2 (B), and furin (C). The arrows indicate a strong immunochemical positive signal. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.
Figure 4 The submandibular gland. Immunohistochemical expression of ACE2 (A), TMPRSS2 (B), and furin (C). The arrows indicate a strong immunochemical positive signal. Scale bar = 100 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.CC BY · PubMed Central
Figure 5 Band signals showing the protein expression levels of TMPRSS2 (A,B) and furin (C) via Western blot analysis, and a graph showing the intensity of the band area determined using Image J. TMPRSS2, transmembrane protease serine 2.
Figure 5 Band signals showing the protein expression levels of TMPRSS2 (A,B) and furin (C) via Western blot analysis, and a graph showing the intensity of the band area determined using Image J. TMPRSS2, transmembrane protease serine 2.CC BY · PubMed Central
Figure 6 Expression and localization of ACE2, TMPRSS2, and furin mRNA and protein in human fungiform papillae taste cells. (A) RT-PCR analysis showing glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ACE2, TMPRSS2, and furin in human fungiform papillae taste cells. (B) Immunochemical staining for ACE2 (green), TMPRSS2 (green), furin (green), and the nucleus (blue) in human fungiform papillae taste cells. The negative control section was stained with non-immunized rabbit IgG. Scale bar = 30 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.
Figure 6 Expression and localization of ACE2, TMPRSS2, and furin mRNA and protein in human fungiform papillae taste cells. (A) RT-PCR analysis showing glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ACE2, TMPRSS2, and furin in human fungiform papillae taste cells. (B) Immunochemical staining for ACE2 (green), TMPRSS2 (green), furin (green), and the nucleus (blue) in human fungiform papillae taste cells. The negative control section was stained with non-immunized rabbit IgG. Scale bar = 30 µm. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2.CC BY · PubMed Central

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Metadata

Authors
Sakaguchi, W., Kubota, N., Shimizu, T., Saruta, J., Fuchida, S., Kawata, A., Yamamoto, Y., Sugimoto, M., Yakeishi, M., & Tsukinoki, K.
Affiliations
  • Kanagawa Dental University (JP)
  • Kanagawa Dental University Junior College (JP)
  • Tokyo Medical University (JP)
Corresponding author
Saruta, Juri
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-08-20
Volume
21
Issue
17
Pages
6000
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21176000
PMC
PMC7503451
OpenAlex
W3078858731
Cited by
200
References
38
Citations by year
2026: 8 · 2025: 14 · 2024: 19 · 2023: 45 · 2022: 45 · 2021: 66 · 2020: 3
FWCI
5.21
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (20H05743, 19K10427, 18K17035)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Dentistry › General Dentistry › Dental Research and COVID-19
  • Health Sciences › Medicine › Dermatology › Dermatological and COVID-19 studies
Keywords
SARS-CoV-2, ACE2, TMPRSS2, furin, viral entry, oral cavity, tongue, gingiva, saliva, tongue coating, stratified squamous epithelium, taste buds, protease inhibitors, COVID-19 pandemic
MeSH terms
Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Gingiva, Humans, Peptidyl-Dipeptidase A, Mouth Mucosa, Pneumonia, Viral, Saliva, Serine Endopeptidases, Tongue, Coronavirus Infections, Furin, Virus Internalization, Pandemics, Spike Glycoprotein, Coronavirus

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