ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal–Oral Routes

Zhong, Mei; Lin, Bingpeng; Pathak, Janak L.; Gao, Hongbin; Young, Andrew; Wang, Xinhong; Liu, Chang; Wu, Kang; Liu, Mingxiao; Chen, Jian Ming; Huang, Jiangyong; Lee, Learn‐Han; Qi, Cui Ling; Ge, Linhu; Wang, Lijing

doi:10.3389/fmed.2020.580796

Cited by 67 publications

(86 citation statements)

References 45 publications

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“…While SARS-CoV-2 infection is noted in oral cavity, in salivary glands, gingiva, oral mucosa and saliva 16 , no one has yet published on taste tissue. Furthermore, previous studies 16 , 26 , 27 did not address the cellular location of ACE2 within human taste buds using the highly specific techniques of ISH (mRNA) and IFS (protein). Taste buds do not contain a resident immune system 28 and TRCs account for all cells within taste buds.…”

Section: Discussionmentioning

confidence: 99%

Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Doyle

Appleton

Liu

et al. 2021

The American Journal of Pathology

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Chemosensory changes are well-reported symptoms of SARS-CoV-2 infection. The virus targets cells for entry by binding of its spike protein to cell-surface angiotensin-converting enzyme- 2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization (ISH) probe and an antibody specific to ACE2, ACE2 is present on a subpopulation of TRCs, namely, Type II cells in taste buds in taste papillae. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19, including taste changes, were biopsied. Based on ISH, replicating SARS-CoV-2 was present in Type II cells. Therefore, taste Type II cells provide a potential portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of the patient’s FP taste stem cell layer were disrupted during infection and had not completely recovered 6 weeks post symptom onset. Another patient suffering post-COVID-19 taste disturbances also had disrupted stem cells. These results demonstrate the possibility that novel and sudden taste changes frequently reported in COVID-19 may be the result of direct infection of taste papillae by SARS-CoV-2. This may result in impaired taste receptor stem cell activity and suggest more work is needed to understand the acute and post-acute dynamics of viral kinetics in the human taste bud.

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Section: Discussionmentioning

confidence: 99%

Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Doyle

Appleton

Liu

et al. 2021

The American Journal of Pathology

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“…The expression of ACE2 in the tongue, lip, and cheek has been stated by Sawa [73]. Chen et al discovered that ACE2 is expressed in salivary glands [74]. Finally, the immunohistochemistry results reported by Zhong et al showed that the anatomical areas with the highest expression of ACE2 from highest to lowest were lip, tongue, buccal mucosa, and gingival and palatal tissue.…”

Section: Ace2 Expression In T2dmmentioning

confidence: 83%

“…The expression and distribution of ACE2 in the human body may indicate potential SARS-CoV-2 infection routes, which have major implications for understanding pathogenesis and designing therapeutic strategies [67]. Some studies have shown that ACE2 is potentially expressed in the oral cavity and is highly enriched in epithelial cells [68][69][70][71][72][73][74][75]. According to Xu et al, ACE2 expression was shown to be slightly higher in the oral tongue than in other oral tissues.…”

Section: Ace2 Expression In T2dmmentioning

confidence: 99%

Should We Be Concerned about the Association of Diabetes Mellitus and Periodontal Disease in the Risk of Infection by SARS-CoV-2? A Systematic Review and Hypothesis

et al. 2021

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The objective of this article was to conduct a systematic review of the literature to contrast the existing evidence regarding the relationship between periodontal disease (PD) and diabetes mellitus (DM) with the possibly increased risk of SARS-CoV-2 infection, as well as to establish a hypothesis that explains the ways in which this interaction could take place. A literature search up from 1 January 2020 to 21 March 2021 was conducted in three electronic databases, namely, PubMed, Web of Science, and Scopus, in order to identify studies on periodontal disease alone or in conjunction with diabetes mellitus, reporting any relation with SARS-CoV-2 infection as a primary outcome. Only articles published in the English language were included. Due to the lack of studies, we decided to collect all the theoretical and clinical evidence suggesting a possible biological pathway evidencing the relationship among PD, DM, and SARS-CoV-2 infection. From a total of 29 articles, 12 were included for final review studies (five reviews, two hypotheses, one Special Issue, one perspective, one commentary, one case–control study, and one case report). In addition, this systematic review article hypothesizes the correlation between PD and type 2 diabetes mellitus (T2DM) by expression of angiotensin-converting enzyme 2 (ACE2) in periodontal tissue and the risk of SARS-CoV-2 infection. T2DM is a metabolic disorder characterized by high blood glucose levels resulting from altered insulin secretion or action. Likewise, periodontitis and T2DM are inflammatory disorders with a bidirectional association, and both diseases have a similar immunomodulatory cascade and cytokine profile. ACE2 is a crucial component of the renin–angiotensin system (RAS) and the key factor of entry in the cells by the new SARS-CoV-2. ACE2 is widely distributed in the lung and kidneys, and interestingly has a great distribution in the oral cavity, principally in the tongue and periodontal tissue. ACE2 in periodontal tissue plays a crucial role between health and disease. Moreover, the ACE2/Ang-(1-7)/MasR axis is downregulated in the dysbiotic and inflammatory periodontal environment. Nevertheless, the balance of ACE2 activity is modified in the context of concurrent diabetes, increasing the expression of ACE2 by the uncontrolled glycemia chronic in T2DM. Therefore, the uncontrolled hyperglycemia possibly increases the risk of developing periodontitis and triggering overexpression of ACE2 in periodontal tissue of T2DM patients, with these events potentially being essential to SARS-CoV-2 infection and the development of mild-to-severe form of COVID-19. In this sense, we would like to point out that the need for randomized controlled trials is imperative to support this association.

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“…Only one study focused on identifying the presence of SARS-CoV-2 in oral tissues by means of PCR. The study design most used was “in silico”, followed by “in vivo” and finally “in vitro” [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Most of the articles showed a combination of two or more of the aforementioned study designs.…”

Section: Resultsmentioning

confidence: 99%

Presence of SARS-CoV-2 and Its Entry Factors in Oral Tissues and Cells: A Systematic Review

et al. 2021

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Background and Objectives: The aim of this systematic review is to summarize the current data about the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its entry factors in oral tissues and cells. Materials and Methods: This systematic review was carried out based on the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA). Three databases were analyzed (Pubmed, Web of science and Scopus) by three independent researchers. From the 18 identified studies, 10 of them met the inclusion criteria. The presence of SARS-CoV-2 or its entry factors (angiotensin-converting enzyme II (ACE2), transmembrane serine proteases (TMPRSS), and furin) was analyzed in these 10 studies during the pandemic. Results: ACE2 expression was analyzed in 9 of the 10 studies. ACE2 is expressed mainly in the tongue, oral mucosa, salivary glands and epithelial cells. The expression of the TMPRSS2 gene or protein was analyzed in 6 studies. These studies reported that the expression of TMPRSS2 was mainly in the salivary glands, tongue, sulcular epithelium and oral mucosa; as well as in cells of the salivary glands (ductal, acinar and myoepithelial cells) and the tongue (the spinous-based cell layer, horny layer and the epithelial surface). Other TMPRSS were also reported. The expression of TMPRSS3, TMPRSS4, TMPRSS5, TMPRSS7 and TMPRSS11D was reported mainly in salivary glands and in epithelial-type cells. Furan expression was analyzed in three studies. The expression of furin was detected mainly in epithelial cells of the tongue. A variety of methods were used to carry out the detection of SARS-CoV-2 or its input molecules. Conclusions: These results show that SARS-CoV-2 can infect a wide variety of oral tissues and cells, and that together with the theories dedicated to explaining the oral symptoms present in SARS-CoV-2 positive patients, it provides us with a good scientific basis for understanding the virus infection in the oral cavity and its consequences.

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ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal–Oral Routes

Cited by 67 publications

References 45 publications

Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Human Type II Taste Cells Express Angiotensin-Converting Enzyme 2 and Are Infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Should We Be Concerned about the Association of Diabetes Mellitus and Periodontal Disease in the Risk of Infection by SARS-CoV-2? A Systematic Review and Hypothesis

Presence of SARS-CoV-2 and Its Entry Factors in Oral Tissues and Cells: A Systematic Review

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