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      Pathological changes in oral epithelium and the expression of SARS-CoV-2 entry receptors, ACE2 and furin

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          Abstract

          Background

          Expression of angiotensin-converting enzyme (ACE)-2 and co-factors like furin, play key-roles in entry of SARS-CoV-2 into host cells. Furin is also involved in oral carcinogenesis. We investigated their expression in oral pre-malignant/malignant epithelial pathologies to evaluate whether ACE2 and furin expression might increase susceptibility of patients with these lesions for SARS-CoV-2 infection.

          Methods

          Study included normal oral mucosa (N = 14), epithelial hyperplasia-mild dysplasia (N = 27), moderate-to-severe dysplasia (N = 24), squamous cell carcinoma (SCC, N = 34) and oral lichen planus (N = 51). Evaluation of ACE2/furin membranous/membranous-cytoplasmic immunohistochemical expression was divided by epithelial thirds (basal/middle/upper), on a 5-tier scale (0, 1—weak, 1.5 –weak-to-moderate, 2—moderate, 3—strong). Total score per case was the sum of all epithelial thirds, and the mean staining score per group was calculated. Real time-polymerase chain reaction was performed for ACE2-RNA. Statistical differences were analyzed by One-way ANOVA, significance at p<0.05.

          Results

          All oral mucosa samples were negative for ACE2 immuno-expression and its transcripts. Overall, furin expression was weakly present with total mean expression being higher in moderate-to-severe dysplasia and hyperplasia-mild dysplasia than in normal epithelium (p = 0.01, each) and SCC (p = 0.008, p = 0.009, respectively).

          Conclusions

          Oral mucosa, normal or with epithelial pathologies lacked ACE2 expression. Furin was weak and mainly expressed in dysplastic lesions. Thus, patients with epithelial pathologies do not seem to be at higher risk for SARS-CoV-2 infection. Overall, results show that oral mucosae do not seem to be a major site of SARS-CoV-2 entry and these were discussed vis-à-vis a comprehensive analysis of the literature.

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          Most cited references50

          • Record: found
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          A new coronavirus associated with human respiratory disease in China

          Fan Wu, Su Zhao, Bin Yu … (2020)
          Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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            Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

            I Hamming, W Timens, MLC Bulthuis … (2004)
            Abstract Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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              Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

              Wenhui Li, Michael Moore, Natalya Vasilieva … (2003)
              Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells 1,2 . Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2) 3,4 , isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. Supplementary information The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Osnat Grinstein-Koren: Role: ConceptualizationRole: InvestigationRole: ResourcesRole: Writing – original draft
                Michal Lusthaus: Role: InvestigationRole: Project administration
                Hilla Tabibian-Keissar: Role: Investigation
                Ilana Kaplan: Role: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Amos Buchner: Role: ValidationRole: Writing – review & editing
                Ron Ilatov: Role: Investigation
                Marilena Vered:
                ORCID: https://orcid.org/0000-0003-1187-2333
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: Writing – original draft
                Ayelet Zlotogorski-Hurvitz: Role: ConceptualizationRole: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draft
                Cheorl-Ho Kim: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS One
                Journal ID (publisher-id): plos
                Title: PLOS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 March 2024
                Publication date Collection: 2024
                Volume: 19
                Issue: 3
                Electronic Location Identifier: e0300269
                Affiliations
                [1 ] Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, Goldschleger School of Dental Medicine, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
                [2 ] Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
                [3 ] Institute of Pathology, Rabin Medical Center, Petach-Tikva, Israel
                [4 ] Goldschleger School of Dental Medicine, Tel-Aviv University, Tel-Aviv, Israel
                [5 ] Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Petach-Tikva, Israel
                Sungkyunkwan University and Samsung Advanced Institute of Health Science and Technology (SAIHST), REPUBLIC OF KOREA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-1187-2333
                Article
                Publisher ID: PONE-D-23-28297
                DOI: 10.1371/journal.pone.0300269
                PMC ID: 10942036
                PubMed ID: 38489333
                SO-VID: 0b04434d-f9a5-4b40-af47-3924d9387173
                Copyright © © 2024 Grinstein-Koren et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 29 September 2023
                Date accepted : 24 February 2024
                Page count
                Figures: 5, Tables: 0, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004375, Tel Aviv University;
                Award ID: 100
                Award Recipient :
                ORCID: https://orcid.org/0000-0003-1187-2333
                The study was supported by the Herb and Ed Stein Chair in Oral Pathology, Tel Aviv University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Biology and life sciences
                Subject: Microbiology
                Subject: Medical microbiology
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Medicine and health sciences
                Subject: Pathology and laboratory medicine
                Subject: Pathogens
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Epithelium
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Epithelium
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Epithelial Cells
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Epithelium
                Subject: Epithelial Cells
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Epithelium
                Subject: Epithelial Cells
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Signs and Symptoms
                Subject: Dysplasia
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Carcinoma
                Subject: Squamous Cell Carcinoma
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Salivary Glands
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Salivary Glands
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Exocrine Glands
                Subject: Salivary Glands
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Exocrine Glands
                Subject: Salivary Glands
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Signs and Symptoms
                Subject: Lesions
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Virology
                Subject: Viral Transmission and Infection
                Subject: Host Cells
                Custom metadata
                Data Availability All relevant data are within the manuscript and its Supporting Information files.
                Outbreaks COVID-19

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