|Year : 2021 | Volume
| Issue : 1 | Page : 39-42
Chronic Periodontal Disease and COVID – 19 Complications: Mechanistic Links Through Increase of CD14+ CD16+ Monocytes Blood Count
Raghunathan Jagannathan1, Thodur Madapusi Balaji2, Swaminathan Rajendran2, V. Raj Prabhu3, Saranya Varadarajan4, Supraja Ajitkumar5
1 Department of Periodontics, Tagore Dental College and Hospital, Chennai, India
2 Department of Dentistry, Bharathirajaa Hospital and Research Institute, T Nagar, Chennai, India
3 Mylai Dental and Implant Centre, Chennai, India
4 Department of Oral Pathology and Microbiology, Sri Venkateswara Dental College and Hospital, Chennai, India
5 Department of Periodontology, Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
|Date of Submission||04-Aug-2020|
|Date of Decision||19-Aug-2020|
|Date of Acceptance||08-Sep-2020|
|Date of Web Publication||2-Mar-2021|
Department of Periodontics, Tagore Dental College and Hospital Chennai
Source of Support: None, Conflict of Interest: None
Introduction: It is well known that the SARS-CoV-2 virus that causes COVID-19 could enter the human host through the oral cavity. In patients with periodontal disease, there is an increase of Furin, Cathepsin, and CD14+ CD16+ monocytes. The hypothesis stated here sheds light on the regular need of periodontal management to reduce inflammation and the levels of deleterious host enzymes and cytokines, which could pave the way for deadly viral diseases such as COVID-19. The Hypothesis: Patients with periodontal disease are at increased risk of SARS-CoV-2 infection due to elevated levels of Furin and Cathepsin in oral cavity and COVID-19 complications like cytokine storm could occur with increased frequency in patients with periodontal disease due to the significant increase of CD14+ CD16+ monocytes in blood. Evaluation of the Hypothesis: Oral and periodontal examination of patients with mild, moderate, and severe SARS-CoV-2 infection could shed light on the significant role played by periodontal disease in making an individual more prone to get SARS-CoV-2 infection by elevation of Furin and Cathepsin and the elevation of CD14+CD16+ monocytes and proinflammatory cytokines in the blood that could consequently worsen COVID-19 complications like cytokine storm. The blood counts of CD14+CD16+ monocytes need to be assayed in SARS-CoV-2 patients with and without periodontal disease to observe if periodontal disease as a coexisting condition elevates the proportion of CD14 CD16+ monocytes in SARS-CoV-2 patients. In fact, assessment of monocyte subsets in peripheral blood could be used as an immunosurveillance marker in SARS-CoV-2 patients. Hence, SARS-CoV-2 positive patients with chronic periodontal disease should be closely monitored for potential signs of a cytokine storm and its related complications.
Keywords: COVID-19, CD14+ CD16+ monocytes, chronic periodontitis
|How to cite this article:|
Jagannathan R, Balaji TM, Rajendran S, Prabhu VR, Varadarajan S, Ajitkumar S. Chronic Periodontal Disease and COVID – 19 Complications: Mechanistic Links Through Increase of CD14+ CD16+ Monocytes Blood Count. Dent Hypotheses 2021;12:39-42
|How to cite this URL:|
Jagannathan R, Balaji TM, Rajendran S, Prabhu VR, Varadarajan S, Ajitkumar S. Chronic Periodontal Disease and COVID – 19 Complications: Mechanistic Links Through Increase of CD14+ CD16+ Monocytes Blood Count. Dent Hypotheses [serial online] 2021 [cited 2022 Jun 27];12:39-42. Available from: http://www.dentalhypotheses.com/text.asp?2021/12/1/39/310530
| Introduction|| |
The COVID-19 global pandemic caused by the SARS-CoV-2 virus has created havoc in many parts of the world and has caused significant morbidity and mortality to scores of human beings. The etiological agent of this lethal infection is an RNA virus that belongs to Coronaviridae family., The nomenclature corona virus has been conferred to this infectious agent by virtue of the presence of a spike glycoprotein structure on the outer envelope of the virus that is used by the virus to enter the host. The nasal cavity is susceptible to SARS-CoV-2 entry and colonization due to the presence of certain ambient conditions. Recently, researchers have established the oral cavity as another important portal of SARS-CoV-2 entry.  The oral cavity is a part of the digestive system and performs a spectrum of functions in human physiology. It is well known that the periodontium, composed by the gingiva, root cementum, alveolar bone, and periodontal fiber apparatus forms an integral part of the oral cavity supporting the teeth and aiding in mastication. Periodontal disease forms one of the prevalent oral diseases that cause significant functional impact. This multifactorial inflammatory disease is predominantly caused by pathogenic bacteria in the dental plaque biofilm that causes gingival inflammation, tooth mobility, and edentulism if left untreated. With regard to the pathobiology of periodontal disease, a protracted inflammatory response coupled with aberrant production of cytokines, inflammatory mediators, and reactive oxygen species play a pivotal role in mediating tissue destruction. It is noteworthy that proteolytic enzymes such as Furin, Cathepsin L, and Cathepsin G are produced during the pathogenesis of periodontal disease by inflammatory and immune cells to mediate tissue destruction. The abovementioned point is of primary importance with regard to the oral cavity as a portal of entry for SARS-CoV-2. It has been demonstrated that the spike glycoprotein of the SARS-CoV-2 virus binds to angiotensin converting enzyme 2 (ACE 2), which is regarded as a receptor for the viral entry mechanism. Abundant ACE 2 expression has been demonstrated in the oral mucosa by molecular docking and genetic expression studies. Along with ACE 2 expression, the presence of proteolytic enzymes such as Furin, Cathepsin L is also a prerequisite as these enzymes cleave the S glycoprotein into S1 and S2 subunits to facilitate entry into host cells. As described above, the presence of periodontal disease could increase significant risk for SARS-CoV-2 infection considering the over expression of Furin and Cathepsin in sites with active periodontal disease.
With regard to post SARS-CoV-2 entry events, the cytokine storm is a significant phenomenon that occurs in the alveolar epithelial cells of the lung, characterized by aberrant overproduction of cytokines such as interleukin 1 beta (IL1-beta) and tumor necrosis factor (TNF) that cause alveolar epithelial cell damage and pneumonia. The systemic impact of cytokine storm is multiorgan damage leading to morbidity and mortality. It is noteworthy that patients with periodontal disease have high levels of pro inflammatory cytokines in their gingival tissue, saliva, gingival crevicular fluid, and blood., It is also well known that periodontal disease has been linked to systemic diseases, multiorgan damage and that this is a cause-consequence link.,,,, The source of cytokines in periodontal pathogenesis is attributed to their production by immune cells mainly monocytes and macrophages following microbial challenge., Monocytes are a heterogeneous population of immune cells that exist in three subsets namely, classical CD 14++ CD 16- (high CD 14 expression with no CD 16 expression), intermediate CD 14++ CD 16+ (high expression of CD 14 and low expression of CD 16), and nonclassical CD 14+ CD 16+ (low expression of CD 14 and CD 16). It has been documented that the number of nonclassical monocytes is elevated both in the gingival tissues and blood samples of chronic periodontitis patients. The basis of this increase is attributed to the systemic bacteremia caused by chronic periodontal disease. Coincidently, institutionalized intensive care unit patients with severe SARS-CoV-2 infection have higher levels of CD14+CD16+ monocytes in peripheral blood. The abovementioned findings highlight the pivotal role played by monocytes in the pathogenesis of periodontal disease and SARS-CoV-2 infection. With the available background information, the present hypothesis aims to assess the role of periodontal disease as a potent risk factor for SARS-CoV-2 infection and its associated complications. A null hypothesis that could be proposed for this specific aim is that periodontal disease is neither a risk factor nor a complicating factor in SARS-CoV-2 infection.
| The Hypothesis|| |
We hypothesize that patients with periodontal disease are at increased risk of SARS-COV-2 infection due to elevated levels of Furin and Cathepsin in the oral cavity. It could also be hypothesized that COVID- 19 complications could occur with increased frequency in patients with periodontal disease due to the significant increase of CD14+ CD16+ monocytes. This could be explained on the basis of the fact that nonclassical monocytes when challenged with infectious stimuli can produce up to three-fold higher levels of the proinflammatory cytokines such as TNF. It has been previously demonstrated that the CD14+ CD16+ nonclassic monocyte subsets produced three-fold higher amounts of TNF protein after stimulation with lipopolysaccharide of Salmonella More Details minnesota, and it further increased 10-fold higher after stimulation with Pam3Cys. This finding is of paramount importance at this point in time, highlighting the systemic impact created by periodontal disease. Also, it has been found that nonclassical monocytes can retain phenotypic and functional properties upon transforming into macrophages. It is hence plausible that a patient with periodontal disease having high circulating levels of nonclassical monocytes could also harbor macrophages of the same phenotype as the nonclassical monocytes in various tissues. With reference to a patient with periodontal disease having SARS-CoV-2 infection, it can be hypothesized that the lung would definitely have a higher population of macrophages with a nonclassical trait. Hence, the cytokine storm phenomenon following SARS-CoV-2 entry into the lung could manifest in a more intense fashion in the abovementioned scenario [Figure 1]. High-circulating levels of cytokines and proinflammatory mediators in patients with periodontal disease could add a synergistic effect if these patients are afflicted by SARS-CoV-2, thereby abnormally raising the concentrations of cytokines.
|Figure 1 Chronic periodontitis mediated risk of cytokine storm in SARS-CoV-2 infection.|
Click here to view
| Evaluating the Hypothesis|| |
Oral and periodontal examination of patients with mild, moderate, and severe SARS-CoV-2 infection could shed light on the significant role played by periodontal disease as a comorbidity for SARS-CoV-2 complications. The counts of CD14+CD16+ monocytes need to be assayed in SARS-CoV-2 patients with and without periodontal disease to observe if periodontal disease as a coexisting condition elevates the proportion of CD14 CD16+ monocytes in SARS-CoV-2 patients. In fact, assessment of monocyte subsets in peripheral blood could be used as an immunosurveillance marker to in SARS-CoV-2patients.It would also be worthwhile to assess whether periodontal treatment reduces the proportion of CD14+ CD16+ monocytes in chronic periodontitis patients without SARS-CoV-2 infection. If proven, this hypothesis would hold high validity as routine periodontal examination and management of periodontitis with scaling, root planning, and adjunctive antimicrobial, nutraceutical agents will help circumventing lethal complications of potential infections like SARS-CoV-2., If positive results are obtained from this hypothesis periodontal disease could be considered significant co morbidity for many life-threatening infections. Hence, SARS-CoV-2 positive patients with chronic periodontal disease should be closely monitored for potential signs of cytokine storm and its related complications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats and coronaviruses. Viruses 2019;11:41.
Fehr A.R., Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1-23.
Yuan Y, Cao D, Zhang Y, Ma J, Qi J, Wang Q et al.
Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains. Nat Commun 2017;8:15092.
Sungnak Waradon, Huang Ni, Bécavin Christophe, Berg Marijn, Queen Rachel, Litvinukova et al.
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26:1-7.
Herrera D, Serrano J, Roldán S, Sanz M. Is the oral cavity relevant in SARS-CoV-2 pandemic? Clin Oral Investig 2020;24:2925-30.
Könönen E, Gursoy M, Gursoy UK. Periodontitis: a multifaceted disease of tooth-supporting tissues. J Clin Med 2019;8:1135.
Balaji SK, Lavu V, Rao S. Chronic periodontitis prevalence and the inflammatory burden in a sample population from South India. Indian J Dent Res 2018;29:254-9.
] [Full text]
Meyle J., Chapple I. Molecular aspects of the pathogenesis of periodontitis. Periodontol 2000. 2015;69:7–17.
Madapusi Balaji T, Varadarajan S, Rao USV, Raj AT, Patil S, Arakeri G et al.
Oral cancer and periodontal disease increase the risk of COVID 19? A mechanism mediated through Furin and Cathepsin overexpression. Med Hypotheses 2020;144:109936.
Renhong Yan, Yuanyuan Zhang, Yaning Li, Lu Xia, Yingying Guo, Qiang Zhou. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-48.
Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X et al.
High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12:8.
Lin B, Zhong M, Gao H, Wu K, Liu M, Liu C et al.
Significant expression of FURIN and ACE2 on oral epithelial cells may facilitate the efficiency of 2019-nCov entry. BioRxiv. 2020.
Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev 2020;53:25-32.
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;80:607-13.
Barros SP, Williams R, Offenbacher S, Morelli T. Gingival crevicular fluid as a source of biomarkers for periodontitis. Periodontol 2000 2016;70:53-64.
Silva N, Abusleme L, Bravo D, Dutzan N, Garcia-Sesnich J, Vernal R et al.
Host response mechanisms in periodontal diseases. J Appl Oral Sci 2015;23:329-55.
Patini R. Oral Microbiota: Discovering and Facing the New Associations with Systemic Diseases. Pathogens 2020;9:313.
Isola G, Giudice AL, Polizzi A, Alibrandi A, Patini R, Ferlito S. Periodontitis and tooth loss have negative systemic impact on circulating progenitor cell levels: a clinical study. Genes (Basel) 2019; 10: 1022.
Mohammed H, Varoni EM, Cochis A, Cordaro M, Gallenzi P, Patini R et al.
Oral dysbiosis in pancreatic cancer and liver cirrhosis: a review of the literature. Biomedicines 2018;6:115.
Patini R, Staderini E, Lajolo C, Lopetuso L, Mohammed H, Rimondini L et al.
Relationship between oral microbiota and periodontal disease: a systematic review. Eur Rev Med Pharmacol Sci 2018;22:5775-88.
Patini R, Gallenzi P, Spagnuolo G, Cordaro M, Cantiani M, Amalfitano A et al.
Correlation between metabolic syndrome, periodontitis and reactive oxygen species production. A pilot study. Open Dent J 2017;11:621-27.
Isola G, Polizzi A, Santonocito S, Alibrandi A, Ferlito S. Expression of salivary and serum malondialdehyde and lipid profile of patients with periodontitis and coronary heart disease. Int J Mol Sci 2019;20:6061.
Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN et al.
Nomenclature of monocytes and dendritic cells in blood. Blood 2010;116:e74-80.
Jagannathan R, Lavu V, Rao SR. Comparison of the proportion of non-classic (CD14+CD16+) monocytes/macrophages in peripheral blood and gingiva of healthy individuals and patients with chronic periodontitis. J Periodontol 2014;85:852-58.
Nagasawa T, Kobayashi H, Aramaki M, Kiji M, Oda S, Izumi Y. Expression of CD14, CD16 and CD45RA on monocytes from periodontitis patients. J Periodontal Res 2004;39(1):72-8.
Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y et al.
Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev 2020;7:998-1002.
Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B et al.
The proinflammatory CD14+ CD16+DR++ monocytes are a major source of TNF. J Immunol 2002;168:3536–42.
Frankenberger M, Hofer TPJ, Marei A, Dayyani F, Schewe S, Strasser C et al.
Transcript profiling of CD16-positive monocytes reveals a unique molecular fingerprint. Eur J Immunol 2012;42:957-74.
Sahni V, Gupta S. COVID-19 &Periodontitis: The cytokine connection. Med Hypotheses 2020;144:109908.
Isola G, Polizzi A, Iorio-Siciliano V, Alibrandi A, Ramaglia L, Leonardi R. Effectiveness of a nutraceutical agent in the non-surgical periodontal therapy: a randomized, controlled clinical trial [published online ahead of print, 2020 Jun 17]. Clin Oral Investig 2020.
Patini R, Mangino G, Martellacci L, Quaranta G, Masucci L, Gallenzi P. The effect of different antibiotic regimens on bacterial resistance: a systematic review. Antibiotics (Basel). 2020;9:22.