{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:59:12Z","timestamp":1790395152042,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global public health emergency. Periodontitis, the most prevalent disease that leads to tooth loss, is caused by infection by periodontopathic bacteria. Periodontitis is also a risk factor for pneumonia and the exacerbation of chronic obstructive pulmonary disease, presumably because of the aspiration of saliva contaminated with periodontopathic bacteria into the lower respiratory tract. Patients with these diseases have increased rates of COVID-19 aggravation and mortality. Because periodontopathic bacteria have been isolated from the bronchoalveolar lavage fluid of patients with COVID-19, periodontitis may be a risk factor for COVID-19 aggravation. However, the molecular links between periodontitis and COVID-19 have not been clarified. In this study, we found that the culture supernatant of the periodontopathic bacterium Fusobacterium nucleatum (CSF) upregulated the SARS-CoV-2 receptor angiotensin-converting enzyme 2 in A549 alveolar epithelial cells. In addition, CSF induced interleukin (IL)-6 and IL-8 production by both A549 and primary alveolar epithelial cells. CSF also strongly induced IL-6 and IL-8 expression by BEAS-2B bronchial epithelial cells and Detroit 562 pharyngeal epithelial cells. These results suggest that when patients with mild COVID-19 frequently aspirate periodontopathic bacteria, SARS-CoV-2 infection is promoted, and inflammation in the lower respiratory tract may become severe in the presence of viral pneumonia.<\/jats:p>","DOI":"10.3390\/ijms22031352","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T09:25:22Z","timestamp":1611912322000},"page":"1352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Expression of the SARS-CoV-2 Receptor ACE2 and Proinflammatory Cytokines Induced by the Periodontopathic Bacterium Fusobacterium nucleatum in Human Respiratory Epithelial Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Yuwa","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihisa","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5639-3902","authenticated-orcid":false,"given":"Noriaki","family":"Kamio","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Yokoe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Oral Surgery, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Iinuma","sequence":"additional","affiliation":[{"name":"Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-4267","authenticated-orcid":false,"given":"Kenichi","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","article-title":"Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and Its Immune Cross-Reactivity with SARS-CoV","volume":"11","author":"Ou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"HLH Across Speciality Collaboration, UK COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An Inflammatory Cytokine Signature Predicts COVID-19 Severity and Survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jaci.2020.05.008","article-title":"Elevated Levels of IL-6 and CRP Predict the Need for Mechanical Ventilation in COVID-19","volume":"146","author":"Herold","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","article-title":"Periodontal Diseases","volume":"366","author":"Pihlstrom","year":"2005","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal Diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6049","DOI":"10.18632\/aging.103000","article-title":"Does Comorbidity Increase the Risk of Patients with COVID-19: Evidence from Meta-Analysis","volume":"12","author":"Wang","year":"2020","journal-title":"Aging"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yamasaki, K., Kawanami, T., Yatera, K., Fukuda, K., Noguchi, S., Nagata, S., Nishida, C., Kido, T., Ishimoto, H., and Taniguchi, H. (2013). Significance of Anaerobes and Oral Bacteria in Community-Acquired Pneumonia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063103"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jiac.2016.09.013","article-title":"Quantitative Detection of Periodontopathic Bacteria in Lower Respiratory Tract Specimens by Real-Time PCR","volume":"23","author":"Nagaoka","year":"2017","journal-title":"J. Infect. Chemother. Off. J. Jpn. Soc. Chemother."},{"key":"ref_12","first-page":"56","article-title":"Anaerobic Infections of the Lung and Pleural Space","volume":"110","author":"Bartlett","year":"1974","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1177\/154405910808700418","article-title":"Oral Health and Mortality Risk from Pneumonia in the Elderly","volume":"87","author":"Awano","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10096-012-1710-y","article-title":"Periodontal Infections and Community-Acquired Pneumonia: A Case-Control Study","volume":"32","author":"Melo","year":"2013","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1177\/0022034519833630","article-title":"Periodontitis Is Associated with Chronic Obstructive Pulmonary Disease","volume":"98","author":"Takeuchi","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.4049\/jimmunol.0802906","article-title":"Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification","volume":"182","author":"Imai","year":"2009","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1007\/s00018-012-0936-2","article-title":"Reactivation of Latent HIV-1 by a Wide Variety of Butyric Acid-Producing Bacteria","volume":"69","author":"Imai","year":"2012","journal-title":"Cell Mol. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.biochi.2011.12.001","article-title":"The Periodontal Pathogen Porphyromonas gingivalis Induces the Epstein\u2013Barr Virus Lytic Switch Transactivator ZEBRA by Histone Modification","volume":"94","author":"Imai","year":"2012","journal-title":"Biochimie"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0140-6736(05)75550-1","article-title":"Oral Care and Pneumonia. Oral Care Working Group","volume":"354","author":"Yoneyama","year":"1999","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.archger.2005.10.004","article-title":"Professional Oral Care Reduces Influenza Infection in Elderly","volume":"43","author":"Abe","year":"2006","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/jcpe.12247","article-title":"Effects of Periodontal Treatment on Lung Function and Exacerbation Frequency in Patients with Chronic Obstructive Pulmonary Disease and Chronic Periodontitis: A 2-Year Pilot Randomized Controlled Trial","volume":"41","author":"Zhou","year":"2014","journal-title":"J. Clin. Periodontol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.diabres.2008.10.016","article-title":"Multi-Center Intervention Study on Glycohemoglobin (HbA1C) and Serum, High-Sensitivity CRP (hs-CRP) After Local Anti-Infectious Periodontal Treatment in type 2 Diabetic Patients with Periodontal Disease","volume":"83","author":"Katagiri","year":"2009","journal-title":"Diabetes Res. Clin. Pr."},{"key":"ref_23","first-page":"CD004714","article-title":"Treatment of Periodontal Disease for Glycaemic Control in People with Diabetes Mellitus","volume":"2015","author":"Simpson","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/cid\/ciaa203","article-title":"Genomic Diversity of Severe Acute Respiratory Syndrome-Coronavirus 2 in Patients with Coronavirus Disease 2019","volume":"71","author":"Shen","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/268462a0","article-title":"n-Butyrate Causes Histone Modification in HeLa and Friend Erythroleukaemia Cells","volume":"268","author":"Riggs","year":"1977","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1182\/blood.V96.12.3847","article-title":"Up-Regulation of costimulatory\/Adhesion Molecules by Histone Deacetylase Inhibitors in Acute Myeloid Leukemia Cells","volume":"96","author":"Maeda","year":"2000","journal-title":"Blood"},{"key":"ref_27","first-page":"3886","article-title":"Cell Cycle-Specific Enhancement of type C Virus Activation by Sodium n-Butyrate","volume":"40","author":"Long","year":"1980","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1741-2358.2012.00637.x","article-title":"Oral Health Care and Aspiration Pneumonia in Frail Older People: A Systematic Literature Review","volume":"30","author":"Vanobbergen","year":"2013","journal-title":"Gerodontology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1046\/j.1532-5415.2001.49113.x","article-title":"Aspiration Pneumonia: Dental and Oral Risk Factors in an Older Veteran Population","volume":"49","author":"Terpenning","year":"2001","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1378\/chest.124.1.328","article-title":"Aspiration Pneumonia and Dysphagia in the Elderly","volume":"124","author":"Marik","year":"2003","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00408-011-9334-z","article-title":"Effect of Aging on Cough and Swallowing Reflexes: Implications for Preventing Aspiration Pneumonia","volume":"190","author":"Ebihara","year":"2012","journal-title":"Lung"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3109\/17549507.2014.882987","article-title":"Impaired Laryngopharyngeal Sensitivity in Patients with COPD: The Association with Swallow Function","volume":"16","author":"Clayton","year":"2014","journal-title":"Int. J. Speech Lang. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.devcel.2020.05.012","article-title":"Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract","volume":"53","author":"Smith","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets Across Tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1902\/jop.2005.76.11-S.2154","article-title":"Involvement of Periodontopathic Anaerobes in Aspiration Pneumonia","volume":"76","author":"Okuda","year":"2005","journal-title":"J. Periodontol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1128\/IAI.00943-13","article-title":"Prevotella intermedia Induces Severe Bacteremic Pneumococcal Pneumonia in Mice with Upregulated Platelet-Activating Factor Receptor Expression","volume":"82","author":"Nagaoka","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1902\/jop.1999.70.7.793","article-title":"Role of Oral Bacteria in Respiratory Infection","volume":"70","author":"Scannapieco","year":"1999","journal-title":"J. Periodontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1172\/JCI114265","article-title":"Neutrophil-Activating peptide-1\/interleukin 8, a Novel Cytokine That Activates Neutrophils","volume":"84","author":"Baggiolini","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/00001432-200306000-00002","article-title":"Host Innate Defenses in the Lung: The Role of Cytokines","volume":"16","author":"Strieter","year":"2003","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10970","DOI":"10.1073\/pnas.2005615117","article-title":"Effective Treatment of Severe COVID-19 Patients with Tocilizumab","volume":"117","author":"Xu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.33594\/000000120","article-title":"The Periodontopathic Bacterium Fusobacterium nucleatum Induced Proinflammatory Cytokine Production by Human Respiratory Epithelial Cell Lines and in the Lower Respiratory Organs in Mice","volume":"53","author":"Hayata","year":"2019","journal-title":"Cell Physiol. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Watanabe, N., Yokoe, S., Ogata, Y., Sato, S., and Imai, K. (2020). Exposure to Porphyromonas gingivalis Induces Production of Proinflammatory Cytokine via TLR2 from Human Respiratory Epithelial Cells. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113433"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Koike, R., Cueno, M.E., Nodomi, K., Tamura, M., Kamio, N., Tanaka, H., Kotani, A., and Imai, K. (2020). Heat-Killed Fusobacterium nucleatum Triggers Varying Heme-Related Inflammatory and Stress Responses Depending on Primary Human Respiratory Epithelial Cell Type. Molecules, 25.","DOI":"10.3390\/molecules25173839"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3201\/eid1003.030571","article-title":"SARS Research Group of National Taiwan University College of Medicine and National Taiwan University Hospital Patient Data, Early SARS Epidemic, Taiwan","volume":"10","author":"Hsueh","year":"2004","journal-title":"Emerg. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1056\/NEJMoa1211721","article-title":"Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia","volume":"367","author":"Zaki","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical Course and Outcomes of Critically Ill Patients with SARS-CoV-2 Pneumonia in Wuhan, China: A Single-Centered, Retrospective, Observational Study","volume":"8","author":"Yang","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1177\/00220345880670120701","article-title":"Composition and Buffer Capacity of Pooled Starved Plaque Fluid from Caries-Free and Caries-Susceptible Individuals","volume":"67","author":"Margolis","year":"1988","journal-title":"J. Dent. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1177\/00220345880670090701","article-title":"Composition of Human Plaque Fluid","volume":"67","author":"Moreno","year":"1988","journal-title":"J. Dent. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1177\/00220345970760010801","article-title":"Short-Chain Carboxylic Acid Concentration in Human Gingival Crevicular Fluid","volume":"76","author":"Niederman","year":"1997","journal-title":"J. Dent. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"587","DOI":"10.21873\/invivo.11811","article-title":"Butyric Acid in Saliva of Chronic Periodontitis Patients Induces Transcription of the EBV Lytic Switch Activator BZLF1: A Pilot Study","volume":"34","author":"Koike","year":"2020","journal-title":"In Vivo"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2334\/josnusd.20-0388","article-title":"Aspiration of Periodontopathic Bacteria Due to Poor Oral Hygiene Potentially Contributes to the Aggravation of COVID-19","volume":"63","author":"Takahashi","year":"2020","journal-title":"J. Oral Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1352\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:17:14Z","timestamp":1760159834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,29]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031352"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031352","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,29]]}}}