Dental Hypotheses

: 2021  |  Volume : 12  |  Issue : 1  |  Page : 28--35

Porphyromonas gingivalis in Periodontitis: A Forgotten Enemy Behind COVID-19 Pandemic

Haryono Utomo1, I Komang Evan Wijaksana2, Chiquita Prahasanti2,  
1 Department of Forensic Dentistry, Faculty of Dental Medicine, Universitas Airlangga, Indonesia
2 Department of Periodontology, Faculty of Dental Medicine, Universitas Airlangga, Indonesia

Correspondence Address:
Chiquita Prahasanti
Departement of Periodontology, Faculty of Dental medicine, Universitas Airlangga, Jln. Moestopo No. 47, Surabaya 60132


Introduction: Theories or hypotheses regarding the connection between COVID-19 and periodontal disease are increasing during the COVID-19 pandemic. COVID-19 has been reported to have adverse outcomes related to the establishment of a cytokine storm, which is similar to the cytokine expression profile and cells involved in periodontitis. Nevertheless, the exact etiology why cytokine storm is vulnerable in COVID-19 as well as periodontitis still not clearly understood. The hypothesis: Recently, the phenomenon of angry macrophages can be explained by M1/M2 macrophage polarization. Periodontitis patients that harbored Porphyromonas gingivalis have a greater M1/M2 ratio than healthy patients, thus have more active M1 macrophages that produce pro-inflammatory cytokines. We hypothesize that periodontal disease could be a burden in defense mechanism toward infectious diseases, particularly the COVID-19. Evaluation of the Hypothesis: Endotoxin tolerance caused by P. gingivalis lipopolysaccharides shifts immune response from T helper (Th)-1 toward Th2, which leads to a less effective antivirus system. This mechanism may explain the connection between COVID-19 and periodontal disease through their cytokine profiles, microbial balance, and M1/M2 homeostasis. Recommendation for maintenance of oral hygiene and periodontal treatment is mandatory in the COVID era.

How to cite this article:
Utomo H, Wijaksana IE, Prahasanti C. Porphyromonas gingivalis in Periodontitis: A Forgotten Enemy Behind COVID-19 Pandemic.Dent Hypotheses 2021;12:28-35

How to cite this URL:
Utomo H, Wijaksana IE, Prahasanti C. Porphyromonas gingivalis in Periodontitis: A Forgotten Enemy Behind COVID-19 Pandemic. Dent Hypotheses [serial online] 2021 [cited 2021 May 18 ];12:28-35
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Theories or hypotheses regarding the connection between COVID-19 and periodontal disease (PD) are increasing during the COVID-19 pandemic. PD comprises a group of diseases involving inflammatory aspects of the host and disrupted immune-regulation that affect periodontal tissues and could have systemic implications. Various factors and comorbidities have been closely associated with PD such as diabetes, obesity, aging, hypertension, cardiovascular disease (CVD), and coronary heart disease (CHD) development.[1],[2] Low serum CD133+/KDR+ levels during periodontitis appear to be linked with the possibility of developing future endothelial dysfunction and CVD risk.[1] Interestingly, these inflammatory aspects of the host and disrupted immune-regulation in PD have been widely associated with progression or severe coronavirus disease 2019 (COVID-19), an illness caused by coronavirus severe acute respiratory syndrome (SARS)-CoV-2. Additionally, the less urgent examination of the oral cavity, oral health history including periodontal status in COVID-19 patients has not been reported.[3],[4]

Periodontal pockets are the major clinical manifestation of periodontitis, a multifactorial inflammatory disease associated with dysbiosis plaque biofilms and characterized by progressive destruction of the tooth‐supporting apparatus.[5] Periodontal pockets are ideal environments for subgingival bacterial biofilms. Porphyromonas gingivalis (P. gingivalis), an anaerobic periodontal pathogen in the periodontal pocket, can involve in host immune system modulation through its whole bacteria, lipopolysaccharides (LPS) and its other bioactive components such as fimbriae, peptidoglycan, and outer membrane vesicles.[6] P. gingivalis bacteria as well as its LPS may disrupt monocytes or macrophages homeostasis, which may explain the connection between COVID-19 and PD through their cytokine connection and M1/M2 homeostasis.[7]

Periodontitis etiology consists of immunological and inflammatory processes that cause dysregulation in the host response due to periodontal bacterial dysbiosis. Periodontitis has been associated with higher serum levels of different inflammatory biomarkers, such as interleukin (IL) 6, prostaglandins, and C-reactive proteins.[2] Another feature in the pathogenesis of periodontitis is the mechanism of oxidative stress through the production of nitric oxide (NO).[2],[8],[9] A number of inflammatory cytokines associated in periodontitis have been shown to play a role in the mechanism of promotion of periodontal tissue destruction. Cytokines such as IL-1, IL-6, and IL-17, both alone and synergized with IL-1β, tumor necrosis factor (TNF)-α, toll-like receptors (TLR), and prostaglandin E2 (PGE2) are shown to stimulate gingival fibroblast, epithelial cells, and macrophages to release pro-inflammatory mediators to control periodontal tissue homeostasis.[10] These inflammatory cytokines altering vascular permeability, which may increasing bacteremia and stimulate fibroblasts and inflammatory cells, which in turn induce other cytokines.[11] The role of homeostasis in the alveolar bone is played by the receptor activator of nuclear factor-kappa B (NF-kB) (RANK) and its ligands (RANKL) and osteoprotegerin.[10],[12] Meanwhile, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ can downregulate NF-kB and suppress several inflammatory cytokines, such as IL-6 and TNF-α.[10],[13]

Cytokine storm is one of the dangerous effects of COVID-19 patients.[14],[15] Coincidentally, Periodontitis has long been recognized for having based on cytokine response, thus may also be related to the cytokine storm since the patients already have increased circulatory pro-inflammatory cytokines in their body, consequently easier to get a cytokine storm.[4] In cytokine storm, many of the components of cytokine expression, which are common in obesity, aging people are also the same profile with periodontitis.[3],[16]

Recently, the COVID-19 and periodontitis has gained major interest in the scientific community.[17] However, the connection between COVID-19 and periodontitis is not well understood. In light of these findings, the aims of this study were to further evaluate a possible association between a PD and COVID-19 through their cytokine profiles, microbial balance, and M1/M2 homeostasis. It is hypothesized that periodontal pocket could be a favorable anatomical niche for the virus and acting as a reservoir for SARS-CoV-2. P. gingivalis and its product may alter monocytes or macrophages homeostasis, which may explain the connection between COVID-19 and PD through their cytokine connection and M1/M2 homeostasis. Thus, optimal periodontal health is mandatory to prevent severe COVID-19 infection.

 The hypothesis

We hypothesize that periodontal pocket could be a favorable anatomical niche for the virus and acting as a reservoir for SARS-CoV-2. P. gingivalis and its product may alter monocytes or macrophages homeostasis, which may explain the connection between COVID-19 and PD through their cytokine connection and M1/M2 homeostasis. The keystone of oral bacteria P. gingivalis has the propensity to disrupt microorganism balance (dysbiosis) which impaired host-immune response as well as decreasing innate immunity against COVID by several pathways: (a) P. gingivalis-induced C5aR1/TLR2 crosstalk in macrophages also inhibits the production of IL-12p70, which needed for stimulating natural killer (NK) cells precursors and interferon (IFN)-γ that are very important in antivirus system;[6],[18],[19] (b) in less IFN-γ niche, the polarization of M1/M2 macrophages and Th1/Th2 immune response are directed to M2 and Th2 that are less effective in virus eradication;[20] (c) prolonged stimulation of LPS elicit endotoxin tolerance which also induces immune response shift to Th2;[7] (d) nonsurgical periodontal treatment leads to decrease in the levels of IL-17 both in the gingival crevicular fluid (GCF) and serum of patients with PD;[4] (e) P. gingivalis inhibits IFN-γ-dependent priming of macrophages and their NO-dependent pathway for intracellular killing, without affecting the overall ability of macrophages to elicit inflammatory responses; and (f) P. gingivalis minimizing the ability for T-cell immunomodulatory influx into the lesions.[7] Unfortunately, since these inhibitory effects in turn cause suppression of inducible nitric oxide synthase (iNOS)-dependent macrophage[21] killing of P. gingivalis, the population still mostly intact, thus periodontal therapy is still needed. Additionally, the periodontal treatment also cleanses the periodontal pockets that may harbor pathogens.

 Evaluation of the hypothesis

COVID-19 cytokine storm immunopathogenesis

Cytokine storm is the famous cause of fatality in COVID-19, it is a general term applied to maladaptive cytokine release in response to infection and other stimuli. The pathogenesis is complex but the main idea is the loss of regulatory control of proinflammatory cytokine production, both at local and systemic levels. The disease progresses rapidly, as well as high mortality. During the COVID-19, severe deterioration in some patients has been closely associated with dysregulated and excessive cytokine release. Cytokines play an important role in immunopathology during viral infection followed by a rapid and well-coordinated innate immune response, which is the first line of defense against viral infection. However, dysregulated and excessive immune responses may cause immune damage to the human body.[14],[22] Shreds of evidence from severely ill patients with human coronaviruses (HCoVs) suggest that proinflammatory responses play a role in the pathogenesis of HCoVs. the cells involved secrete low levels of the antiviral factors IFNs and high levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and chemokines (i.e., C-C motif chemokine ligand [CCL]-2, CCL-3).[23]

In classical immunology, cytokine storm also related to angry macrophages.[24] Recently, this concept is updated through the monocyte or macrophage M1/M2 polarization. Macrophage M1 is related to the pro-inflammatory mediators and M2 the anti-inflammatory.[16] These macrophages origin initiates by the monocytes available in the bloodstream, the pro-inflammatory monocytes (Ly6chi) which then becomes M1 macrophage, and patrolling monocytes (Ly6clow) to M2 macrophage. M1 macrophages, also known as classically activated macrophages, can be activated by TLR ligands, such as LPS or IFN-γ.[25],[26] M1 macrophages are characterized by high antigen presentation and high expression of pro-inflammatory cytokines such as IL-12, IL-23, and TNF-α.[27] M1 macrophages are reportedly associated with inflammatory, microbicidal, and tumoricidal activities [Figure 1].[28],[29] M2 macrophages, also called alternatively activated macrophages, can be further divided into the subcategories M2a, M2b, M2c, and M2d. M2a macrophages are induced from nonpolarized naïve macrophages via stimulation with IL-4/IL-13 and downstream involvement of jumonji domain-containing-3 (Jmjd3) and IFN regulatory factor-4.[30] In contrast, M2b macrophages are induced by immunoglobulin complexes in combination with TLR agonists, and M2c macrophages are induced by IL-10, transforming growth factor β, or glucocorticoids.[31] The M2d phenotype, which is only described only in mice, can be induced by adenosine in pro-inflammatory M1 macrophages via activation of the adenosine 2A receptor. M2d macrophages are characterized by increased production of IL-10 and vascular endothelial growth factor and low expression of TNF-α and IL-12.[32]{Figure 1}

Immunohistochemical staining showed decreased numbers of CD4+ and CD8+ T cells in the lymph nodes and spleen. On the other hand, monocytes and macrophages are increased, which may explain elevated levels of pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, and IL-8.[6] The elevated serum cytokine and chemokine levels in Middle East respiratory syndrome (MERS) patients are related to the high number of neutrophils and monocytes in the patients’ lung tissues and peripheral blood, suggesting that these cells may play a role in lung pathology.[33],[34] Similar phenomena have been observed in patients with SARS-CoV infection.[23]

Several observational studies have characterized monocytes during SARS-CoV-2 infection. Zhou et al.[35] found significantly increased circulating proportions of CD14+CD16+ monocytes in peripheral blood from 33 hospitalized patients with diagnosed COVID-19, and this percentage was substantially increased in COVID-19 patients with acute respiratory distress syndrome (ARDS). These monocytes appeared (by CD14 and CD16 staining) to be primarily of the intermediate subtype. Intermediate monocytes make up approximately 5% of the total monocyte population in healthy individuals, but in patients with severe COVID-19, this proportion increased to over 45%.

Vacuolated monocytes with unusual characteristics had been identified by flow cytometric analysis of blood collected from COVID-19 patients. These cells were CD14+CD16+ and expressed a variety of macrophage markers, suggesting some degree of differentiation of monocytes to macrophages in the circulation during SARS-CoV-2 infection. This population of circulating monocytes/macrophages also expressed high levels of cytokines such as IL-6, TNF-α, and IL-10, suggesting a contribution of these cells to cytokine storm, and increased proportions of these cells were associated with increased intensive care unit (ICU) admissions and prolonged time to hospital discharge. The total monocyte population was highly enriched for intermediate and nonclassical subtypes in COVID-19 patients in the same study.[36]

The production of IFN-I or IFN-α/β is the key innate immune defense response against viral infections, and IFN-I is the key molecule that plays an antiviral role in the early stages of viral infection. The delayed release of IFNs in the early stages of SARS-CoV and MERS-CoV infection hinders the body’s antiviral response.[37] Subsequently, the rapidly increased cytokines, and chemokines attract many inflammatory cells, such as neutrophils and monocytes, resulting in excessive infiltration of the inflammatory cells into lung tissue and thus lung injury. It appears from these studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV-infected or MERS-CoV-infected cells could play an important role in the pathogenesis of SARS or MERS.[23]

Chemokines are a family of cytokines that are chemotactic in nature and cause the recruitment of cells of inflammation. Several pathophysiological mechanisms are proposed to explain this phenomenon. One of which is the fact that its symptoms seem to be related to a ‘cytokine storm’ that exhibits itself as elevated serum levels of IL-1 β, IL-7, IL-10, IL-17, IL-2, IL-8, IL-9, granulocyte macrophage colony-stimulating factor (GM-CSF), G-CSF, IFN-gamma, TNF-α, MIP1A, MIP1B, MCP1, and IP10. Patients exhibiting an exaggerated form of symptoms necessitating ICU admission further show even greater levels of IL-2, IL-7, IL-10, IP-10, G-CSF, MIP1A, MCP1, and TNF- α.[3],[34]

Plausibility Role of P. gingivalis on Periodontal Disease, Systemic Diseases, and COVID-19

Over the last decade, there has been an increased interest in the links between periodontitis and systemic diseases.[38] Among them, an association has been demonstrated with major chronic diseases such as cardiovascular diseases, diabetes type 2 (T2DM), metabolic syndrome, rheumatoid arthritis, and obesity.[39] Therefore, the systemic effects of oral pathogens and the role they play in chronic diseases have become a major research focus.

Among the oral bacteria that exhibit systemic effects, P. gingivalis is prominent. It has been detected in several diseased tissues and organs in both humans and animal models. The translocation of P. gingivalis to the distant tissues such as the liver or joint after oral administration and its detection in the brains of patients with Alzheimer disease has led to an increased interest in determining its role in chronic inflammatory diseases.[39] A study which related to the verification of P. gingivalis effects to T2DM and cardiovascular diseases was done by Carter et al.[40] who revealed that P. gingivalis/host interactome was also enriched in a genome-wide association study (GWAS) genes that is a risk factor to atherosclerosis and T2DM. Moreover, in a study Ohtsu et al.[41] reported that ingested P. gingivalis altered the gut microbiota and aggravated glycemic control in streptozotocin‐induced diabetic mice.[41]

Czesnikiewicz-Guzik et al.[42] reported that Th1-type immune responses to P. gingivalis antigens exacerbate angiotensin II-dependent hypertension and vascular dysfunction. In this animal study, systemic T-cell activation, a characteristic of hypertension, was exacerbated by P. gingivalis antigen stimulation. These immune changes in mice with induced Th1 immune responses were associated with an enhanced elevation of blood pressure and endothelial dysfunction compared with control mice in response to 2-week infusion of a suppressor dose of angiotensin II.[42]

The relationship of P. gingivalis and obesity may also relate to the dysbiosis of gut-microbiome. Study by Kato et al.[43] reported that alterations of the gut microbiome underlie metabolic disease pathology by modulating gut metabolite profiles. Their study showed that orally administered P. gingivalis alters the gut microbiome that may be a novel mechanism by which periodontitis increases the risk of various diseases; thus, it is possible that P. gingivalis can affect the metabolites. Metabolite profiling analysis demonstrated that several amino acids related to a risk of developing diabetes and obesity were elevated in P. gingivalis-administered mice.[43]

The P. gingivalis inhibits the production of IL-12p70, which is needed in NK cells precursor, and IFN-γ since repetition of LPS stimulation created endotoxin tolerance.[44] Endotoxin tolerance shifts the immune system from the Th1 (IFN-γ producing cells) toward Th2; unfortunately, the NK and Th1 cells are needed for the antiviral system. The worst thing is that P. gingivalis enhances the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α by macrophages that may relate to the COVID-19 cytokine storm. The systemic effect of LPS for the cytokine storm and endotoxin tolerance had been verified by Utomo[45] in Wistar rats, by injecting LPS in the gingiva. Afterward, TNF-α and IL-4 also increase in nasal and lung tissues as well in serum.[45]

The role of P. gingivalis in inflammatory responses of periodontal tissues and also systemic inflammatory responses lead the needs of treatment options to inhibit the negative effect of the bacteria. The spread of P. gingivalis to systemic could be via blood stream as well as ingestion. The effect of P. gingivalis ingestion was verified.[39],[46] Olsen et al.[18] reported that P. gingivalis also disturbs host-commensal homeostasis and causing dysbiosis of the bacterial community.

Predatory bacteria that selectively predate solely on gram-negative bacteria might be a viable therapeutic alternative for reducing the negative effect of P. gingivalis. The study by Patini et al.[47] demonstrated that predatory bacteria B. bacteriovorus can predate on aerobic species and the microaerophilic conditions, although its predatory capacity was suboptimal in anaerobic conditions. Yu et al.[48] reported that reprogramming of metabolic pathways is critical in governing the polarization of macrophages into classical pro-inflammatory M1 or alternative anti-inflammatory M2 phenotypes in metabolic diseases like diabetes. P. gingivalis, a keystone pathogen of periodontitis, causes an imbalance in M1/M2 activation, resulting in a hyperinflammatory environment that promotes the pathogenesis of periodontitis.[44] P. gingivalis infection modulates metabolic pathways to alter macrophage polarization by inhibition of M2 macrophage activation, thus less anti-inflammatory production since P. gingivalis inhibits α-ketoglutarate, which needed for M2 macrophage polarization. There is also an interesting phenomenon that in the experimental study of M1/M2 macrophage polarization with P. gingivalis, can modulate M1/M2 polarization to M1 macrophages,[44] thus more pro-inflammatory mediators.

P. gingivalis, as an oral pathogen, may have a unique capacity to alter the programming of the M1 macrophage resulting in a hyperinflammatory environment and minimizing the ability for T-cell immunomodulatory influx into the lesions.[48] Consequently, it was not surprising that in severe periodontitis, even already treated, the amount of P. gingivalis is still the majority.[49] Surprisingly, not as predicted before, the induction of other pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF-α) by macrophages is enhanced by the P. gingivalis-induced C5aR1/TLR2 crosstalk and not only by TLR4.[6],[19] Therefore, even in the COVID-19 patients have a Th2 immune response; the cytokine storm of pro-inflammatory cytokines still happens since the complement system (C5a) is in charge of worsening the pro-inflammatory process.

 Periodontal Disease − COVID-19 Connection Hypothesis

Periodontal diseases and certain systemic disorders share similar genetic and/or environmental etiological factors and, therefore, affected individuals may show manifestations of both diseases.[50] Correlations between periodontal disease and systemic diseases are a topic of discussion in the recent scientific literature. The onset of different systemic pathologies, such as rheumatoid arthritis, cardiovascular pathologies, and neurodegenerative pathologies, have been known implicated by P. gingivalis.[51] Patini et al.[52] study showed the correlation between metabolic syndrome and periodontitis through higher reactive oxygen species production.

The penetration and damage of the epithelial layer due to infection of organisms is an important stage in the pathogenesis of PDs. The maintenance of the sulcular area depends on the interaction between the gingival epithelia and the underlying extracellular matrix (ECM) and connective tissue. Transglutaminases (TGs) are one of the enzymes that contribute to the determination of cell shape and play a role in cell adhesion as well as ECM stabilization. TGs are enzymes that catalyze an acyl transfer reaction between the c-carboxamide group of protein-bound glutamine and the e-amino group of lysine residues. In gingiva, TGs contribute to producing a tightened structure, the cornified cell envelope, which is the main component of the epithelial barrier on the surface of the tissue. TG1 isoforms are mainly expressed in stratified squamous epithelia, playing a role in the proliferation and differentiation of terminal keratinocytes. TG2 isoforms is ubiquitously distributed and are involved in cell growth mechanisms/differentiation and apoptosis. TG3 plays an important role in epidermal keratinization and the formation of corned beef envelopes.[11],[53]

Studies show a link between the release of IL-6 and tissue TG, suggesting that TGs-mediated reactions can play a major role in periodontal inflammation.[54] In PDs, TG1 and TG3 isoforms are significantly downregulated. Alteration in TGs mRNA transcription and expression levels lead differentiation of protein content, can occur in damaged tissues of patients with periodontal disease due to their involvement in the remodeling/healing of gingival tissue, and keratinocyte responses. Changes in membrane structure associated with increased active forms of MMP-2 and MMP-9 coincided with significant reductions in mRNA transcriptions and levels of isoform proteins TG1 and TG3. Reduced isoform expression of TG1 and TG3 is associated with gingival tissue structure altered during periodontal disease due to keratinocyte gingival damage and reduced cell adhesion.[11],[53]

Abundant theories as well as hypotheses had been found in the etiopathogenesis of COVID-19 recent journals during the pandemic, to reveal the connection with other diseases or compromises including periodontal disease. Periodontal disease has long been regarded as a silent pandemic that has complex multifactorial pathophysiology with evidence-based claims of immune-mediated pathogenesis. Interestingly, several immunopathogenesis and cells involved also the same as COVID-19. This explained to that elevated levels of cytokines detected in locally inflamed gingival tissue mirror cytokine levels in the systemic circulation.[55]

This similar pathway of inflammatory response pathway toward a possible association between periodontitis- and COVID-19-related adverse effects. Understanding of this correlation prioritizes the importance of keeping PD under check and the value of maintaining meticulous oral hygiene in the COVID-19 era. It also points toward the possibility of the presence of PD as predisposing toward COVID-19-related adverse effects.

 M1/M2 Polarization and Therapeutic Strategies

Macrophages are characterized by remarkable plasticity and versatility, being able to switch from one phenotype to another. This phenomenon results from the macrophages responding to the local niche stimuli encountered in different tissues and activating diverse signaling cascades in response. The differentiation of monocytes to macrophages is primarily controlled by GM-CSF and M-CSF.[36] Furthermore, when macrophages are subsequently present in other tissues, they can respond to local signals with the acquisition of distinct functional phenotypes. Indeed, in response to TLR ligands and IFN-γ, macrophages may undergo pro-inflammatory M1 activation, while they undergo an anti-inflammatory M2 activation after stimulation by IL-4 or IL-13.[56] Therefore, the polarization of macrophages into either the M1 or M2 phenotype has become a promising therapeutic approach for dealing with inflammatory diseases. Specifically, the most common strategies for resolving inflammation are by increasing M2 and/or decreasing M1 polarization ([Figure 1]).[56],[57]

 Consequences of the Hypothesis

Our concept is that optimal periodontal health is mandatory to prevent severe COVID-19 infection. Furthermore, it may be becoming the standard of procedure in the “New Normal” situation to enhance innate immunity against COVID-19 or other inflammatory diseases. However, the collaboration of medical and dental experts, as well as practitioners, are mandatory for the prevention and adjunctive treatment of severe COVID-19 patients. Nevertheless, since this is a dangerous and fatal disease, profound restrictions and safety during treatment is a must.

Moreover, even though it is currently a catastrophe, dentist also must be prepared to combat the spread of SARS-CoV-2 in the post epidemic phase.[58] Even after the critical peak of the outbreak has been overcome, management is needed because cases may still be in the community for months and maybe in years.[59] In some conditions, COVID-19 could be fatal for some categories of patients as special needs ones.[60] Teams of special care dentists must be well prepared to handle the increasing number of patients with unresolved dental problems or unfinished treatment courses, as a consequence of deferred services.[61],[62]


The present study indicated a possible association between a PD and COVID-19 through their cytokine profiles, microbial balance, and M1/M2 homeostasis. Pro-inflammatory cytokine storm can be connected PD and pathogenetic mechanisms of COVID-19. P. gingivalis-induced C5aR1/TLR2 crosstalk in macrophages also inhibits the production of IL-12p70, which needed for stimulating NK cells precursors and IFN-γ that are very important in antivirus system. In less IFN-γ niche, the polarization of M1/M2 macrophages and Th1/Th2 immune response are directed to M2 and Th2 that are less effective in virus eradication. Profound understanding regarding the characteristics of P. gingivalis and its bioactive components and their interaction of host immune modulation may help to invent the best way for preventing COVID-19 disease with fewer side effects.



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Conflict of interest

The authors declare that there are no conflict of interest.


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