Biological Mechanisms of the Potential Association Between Long Covid and Periodontal Disease Development or Progression

1. Introduction

As of September 28 2024, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic that began in March 2020, has led to over 776 million confirmed cases worldwide, with an increase of more than 84,000/week in recent weeks. In the United States alone, over 103 million infections have been reported[1]. The virus has resulted in over 7.06 million deaths globally, with a significant portion—over 1.2 million—occurring in the United States[1]. Furthermore, a meta-analysis of studies conducted through 2022 indicates that Long Covid-related symptoms affect approximately 43% of COVID-19 subjects worldwide[2]. Based on this meta-analysis and Centers for Disease Control and Prevention data, LC’s prevalence ranges from 20% to 31 % in the United States and is prehaps similarly prevalent worldwide[2,3].

Long COVID (LC; aka, post-acute sequelae of SARS-CoV-2 infection (PASC), post-COVID-19, post-acute COVID-19 syndrome, or long-haul COVID)[4,5,6,7], is a multi-organ condition characterized by persistent symptoms in individuals following infection with SARS-CoV-2. More specifically, it is defined as an ongoing pattern of relapsing and remitting changes in the functionality of multiple systems over time. Some definitions of this condition include any new symptoms or medical conditions lasting 30 days or longer following active SARS-CoV-2 infection[8]. Despite intensive effects, there is still no universally accepted case definition for LC. According to the World Health Organization (WHO) Delphi Consensus case definition, LC is identified in individuals with a history of probable or confirmed SARS-CoV-2 infection who continue to experience a variety of symptoms or impairments, such as cognitive dysfunction, fatigue, shortness of breath or others, for nearly three months or more without an alternative diagnosis to explain these symptoms following the onset of the original acute disease[9].

LC can persist regardless of an individual’s vaccination status and is likely to occur even in cases of reinfection with SARS-CoV-2[10]. The condition may persist for several years, increasing private and public health system costs for those affected[11,12,13,14,15,16]. Individuals with LC also face negative impacts on their health-related quality of life, which can lead to loss of income [17,18] and rising personal healthcare expenses[19,20,21,22].

2. LC Reported Symptoms and Clinical Manifestations

LC encompasses a broad spectrum of physical, psychological, and cognitive symptoms. These include fatigue, malaise, muscle pain, dyspnea, memory loss, hair loss, migraines, along with attention and sleep disorders. LC can lead to adverse clinical manifestations across multiple body systems, including but not limited to the respiratory, neurological, cardiovascular, gastrointestinal, metabolic, renal, and reproductive systems[5,14,16,23,24,25,26,27,28]. The disease is typically more pronounced in individuals with weakened immune systems or those who are immunocompromised[29].

3. LC Clinical Manifestations in the Oral Cavity

Although numerous reports have documented oral complications associated with SARS-CoV-2, few have addressed oral manifestations of LC[30]. The symptoms and clinical manifestations of LC may include taste disorders (e.g., hypogeusia or ageusia), chronic oral dysesthesia, ulceration, discoloration, hemorrhagic changes in the oral mucosa, aphthous-like lesions, atrophic cheilitis, alterations in salivary glands, oral mucormycosis, and actinomycotic osteomyelitis[31,32,33,34,35]. To the best of our knowledge, the potential effects of LC on periodontitis—the most common oral disease after dental caries[36]—have been explored only minimally. However, there is significant potential for a strong relationship between these two conditions due to a shared chronic immune and inflammatory status. One cross-sectional study, which used a limited definition of LC, reported a higher prevalence of "sequelae from COVID-19" in individuals with periodontitis and obesity compared to those with obesity alone[37].

4. Periodontitis: Definition and Systemic Impact

Periodontal diseases affect the tissues that protect and support teeth. Most are induced by dental plaque and can be categorized into gingivitis, a periodontal tissue inflammation without loss of attachment or alveolar bone support, and periodontitis. Gingivitis is a reversible response to supragingival dental plaque and has a universal prevalence[38]. In contrast, periodontitis is a chronic condition that results in the loss of attachment and/or alveolar bone, with a prevalence of 42.2 % in the U.S.[39]. Severe periodontitis often results in tooth loss and impacts approximately 7.8% of the U.S. adult population aged 30 and older[39] and 11.2% globally[40]. It contributes to a poor quality of life and is the most common form of bone pathology in humans[41].

Periodontitis has been linked to various systemic conditions, a subfield termed 'periodontal medicine, ' which explores two primary avenues: (A) the contribution of periodontitis to diseases in other parts of the body, facilitated by bacterial migration and the influence of active periodontitis on systemic inflammation, as evidenced by its association with coronary heart disease[42,43]; and (B) how systemic conditions, such as diabetes, influence the immune system and potentially exacerbate periodontitis. Notably, diabetes is recognized as a significant risk factor for periodontitis[44,45,46,47]. Therefore, examining the mechanisms of LC function and their potential impact on periodontal immunity, leading to subgingival dysbiosis and subsequent periodontal damage, forms a hypothesis modeled on the relationship between diabetes and periodontitis.

While it can be argued that there are differences in the systemic and local immune profiles during infections, it is essential to note that advanced periodontitis results in a destructive immune response at both local (gingival) and systemic levels[48,49], exacerbating any other existing systemic inflammation[42,43]. It might worsen the initial COVID-19 infection or increase the likelihood of leukocyte complications[50]. Conversely, the immuno-inflammatory dysregulation associated with LC could promote the onset, progression, and severity of periodontitis, similar to diabetes[51,52].

5. Epidemiologic Factors Shared Between LC and Periodontitis

LC has been reported to occur in individuals exhibiting specific characteristics, such as smokers, the elderly, women, a lower socio-economic status (SES), ethnic minorities, history of severe symptoms during acute COVID-19, preexistent psychiatric disorders, and preexisting chronic comorbidities such as obesity, diabetes, asthma, cardiovascular disease (CVD), and hypertension[2,6,53,54,55]. Periodontitis shares many of these characteristics, like older age, low SES, and a higher prevalence among ethnic minorities[56,57]. Additionally, periodontitis often coexists with conditions prevalent in the LC group, such as chronic mental health disorders and cardiometabolic diseases (e.g., diabetes, CVD, and obesity)[58,59,60,61,62]. Specific population subgroups also exhibit distinct characteristics related to periodontitis, such as low educational attainment, infrequent dental visits, and poor dietary habits[56,57,63,64].

6. Immuno-Pathophysiology Mechanisms Shared by LC and Periodontitis

6.1. Early Immune Response to the SARS-COV-2

6.1.1. Interferon-Mediated Innate Immune Response to a Viral Infection

Under normal conditions, innate immunity tracks any generic viral infection to its source to combat it. This process is mediated by type I interferon (IFN) expression and related molecules and occurs within a couple of hours[65]. It limits viral replication within the infected cells, slows the virus’s spread, and activates the adaptive immune response, which involves the simultaneous actions of B cells generating neutralizing antibodies alongside T cells, including CD4+ and CD8+, which quickly eliminate infected cells and their viral components[65,66,67].

However, during acute SARS-CoV-2 (or initial) infection, this virus can effectively slow down [68] or evade the activation of the immune system related to type I and type III IFN responses, allowing it to continue replicating[69,70,71]. Additionally, the adaptive immune responses are likewise impaired, as the innate immune system cannot quickly present antigenic information[66]. Along with the impaired or delayed type I and type III IFN innate immune regulation[68,72], low dendritic cell counts, a deficit in IFN-α expression[73,74], and a reduction in the total number of NK cells is observed[75], along with the depletion and exhaustion of the surviving NK cells[76].

Dendritic cells (DCs) are the primary source of type I IFN in the gingival tissue, with higher expression in subjects with periodontitis[77]. However, in the complex etiological model of periodontitis, where bacterial and viral challenges can occur simultaneously, a decrease in type I IFN and IFN-γ is observed due to the co-infection of organisms from these two kingdoms[78]. Studies examining the association between Herpesviruses and periodontitis have also found lower levels of IFN among periodontitis patients who tested positive for these viruses [79] or during active periodontitis[80]. It appears that periodontal infection by Herpesviruses and SARS-CoV-2 may share similar mechanisms for evasion or dampening of IFN expression by dendritic cells.

6.1.2. The Short-Term T-Cell Response to SARS-CoV-2

Among SARS-CoV-2 positive asymptomatic individuals, delays in innate immune responses do not hinder long-term viral clearance. The adaptive immune responses, which include increased CD4+ and CD8+ T cell counts and higher levels of neutralizing antibodies, effectively compensate for the impaired innate response. These antibodies are formed faster than usual to combat the viral infection[81]. The presence of active T cells in infected tissues and antibodies produced by B cells against SARS-CoV-2 signifies disease resolution[66,82,83].

Among patients with acute COVID, there is a functional impairment in adaptive immune responses characterized by a decrease in total B cells, CD4+ T cells, and CD8+ T cells (lymphopenia). It is often accompanied by increased survival but functionally exhausted T cells[66,67,76,83,84]. Immature neutrophils particularly disrupt T-cell polarization, promoting Th17 cell differentiation while suppressing Th1. This causes major disturbances in the immune response against SARS-CoV-2[85,86,87]. Key Th17 effector cytokines, including members of the IL-17 family (primarily IL-17A and IL-22), play crucial roles in the pathogenesis of COVID-19 as well as periodontitis [83,88,89,90,91].

Antigen persistence, antibody production, and T-cell counts are directly linked. The stability of CD4 and CD8 T-cell response is one of the findings related to recovery from acute COVID[92,93,94,95,96], with fewer tissue cells presenting T-cell receptors[97]. However, antibody titers against the SARS-CoV-2 may vary in different screened populations, from reduction [92,93,94,95,96] to somatic effects[98]. Local antibody expression will also be elevated in body parts where persistent antigen release is detected, such as in the small bowel[98].

The role of CD 8+T cells in chronic periodontitis is less noticeable. CD8+ T cells appear to contribute to alveolar bone preservation by suppressing osteoclastogenesis[99,100,101]. Nonetheless, their role can be unnoticed by the higher level of other immuno-inflammatory responses mounted against periodontal microbial infections, dramatically uncoupling bone homeostasis. The overreactive immune response under LC can disguise CD8+ role even further[102].

6.1.3. Neutrophils and the “Cytokine Storm”

The immune system uses various strategies to compensate for the impairments caused by severe SARS-CoV-2 infection, including an increase in the neutrophil count[103] as early as the first week[104,105,106]. Neutrophil activation amplifies inflammation, leads to prothrombotic loops and persistent production of pro-inflammatory cytokines such as Interleukins (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, IL-21, IL-23, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF), collectively referred to as the 'cytokine storm'[67,75,106,107,108,109,110]. The persistence of high active neutrophil counts with abnormal responses after the acute phase of COVID is considered a marker of severe LC[111,112,113].

In the periodontium, the pathogenic pathways related to plaque-induced periodontal diseases involve many of the cytokines from the storm, which play relevant roles[114,115]. IL-1β, IL-6, IL-17, IL-23, and TNF are well documented in periodontitis, exerting several roles in immune cell recruitment, pro-inflammatory activity, and periodontal tissue destruction. Conversely, IL-2 and IL-10 promote less inflammation and tissue destruction.

Neutrophil-extracellular traps (NETs) are another inflammatory-enhancing and pro-thrombotic mechanism from these cells[116], in addition to NETs’ primary role as traps for pathogens[116,117]. NETs are composed of the extracellular expression of chromatin with histones, proteases, lactoferrin, cathepsins, and myeloperoxidase[118], and are linked to several chronic diseases, most notably Chronic Obstructive Pulmonary Disease (COPD) and asthma[119]. NETs were detected in the blood of severe COVID patients by several studies[120,121,122].

Circulating NETs, identified by cell-free DNA (cfDNA) or myeloperoxidase (MPO)-DNA in blood, are standard markers of acute diseases, including COVID, and are also present in LC[123]. However, cfDNA or MPO-DNA alone is not a precise NET marker, as it also indicates cell necrosis and apoptosis[124]. The best use of circulating cfDNA/MPO-DNA as a NET marker is alongside tissue biopsies. Despite this, it is suggested that the initial SARS-CoV-2 infection may cause epigenetic shifts in parenchymal, vascular, and immune cells, including myeloid progenitor cells in the bone marrow, leading to neutrophil formation and NETs[123]. These hypotheses remain unconfirmed.

NETs are recognized as integral to the immune response against plaque-induced periodontal diseases[125] characterized by their involvement in the acute phases of inflammation. Biopsies indicate a higher expression of NETs in gingivitis compared to periodontitis[126]. Periodontitis and acute COVID possess similarities regarding elevated cfDNA/MPO-DNA levels associated with an inflammatory response with NETs. MPO-DNA levels increased positively with probing depths and clinical attachment loss, with the highest levels among subjects with periodontitis and Rheumatoid Arthritis[127]. This similarity was postulated as one reason why periodontitis could exacerbate the initial COVID infection[118].

6.1.4. Monocytes and Macrophages

Another key component of the immune response to the SARS-CoV-2 that has a relevant role in periodontitis is monocytes and macrophages, which have been reported to be hyperactivated and dysregulated in association with severe COVID[128,129,130]. Monocytes and macrophages are part of virus clearance; however, their dysregulation exacerbates tissue damage[130,131,132]. Like neutrophils, when active, these cells produce cytokine expression and pyroptosis – inflammation-induced cell death[133,134].

Key inflammatory molecules expressed by these two cells when dysregulated are IL-1α, IL-1β, IL-6, IL-7, THF, IFNs I and II, CCL2, CCL3, CXCL10[130], a molecular profile associated with hyperinflammation and severe diseases[131,135]. Particularly, the elevated systemic IL-6 levels led to the use of this cytokine’s inhibitor as therapeutic drugs against COVID, like Tocilizumab and Siltuximab[123].

Hyperactivation of monocytes and macrophages has been reported in LC[136], potentially causing ongoing tissue damage. Active monocytes were detected from eight to fifteen months[137] of LC, regardless of the severity of the initial or acute infection. Macrophages are histological findings in organs impacted by LC, including the brain, liver, lungs, and adipose tissue[138]. In vitro assays with macrophages from subjects recovered from COVID have demonstrated a persistent hyperregulation in the production of inflammatory molecules and a downregulation of pro-resolving factors[139].

Hyperactive monocytes and macrophages also indicate the inflammatory response in periodontitis[140,141].This finding supports the hypothetical pathway linking periodontitis to cardiovascular diseases[142], which suggests that hyperreactive macrophages from active periodontitis sites could enter the bloodstream and initiate endothelial damage or affect other areas of the body. Thus, in patients with periodontitis infected with SARS-CoV-2, a proinflammatory monocyte/macrophage profile is already present. Conversely, the persistence of this proinflammatory profile in patients can also alter the response to dental plaque, leading to a periodontal destructive pattern.

IL-6 is a key cytokine in periodontitis. High levels in the gingival crevicular fluid (GCF) are associated with alveolar bone loss and dysbiotic biofilms[143,144]. However, in an animal model, IL-6 elevation from gingival epithelial cells was observed during common daily episodes, such as chewing[145] in response to mechanical damage. This IL-6-induced mechanism leads to the priming of resident TH17 cells as the key defense mechanism of that specific mucosal barrier, independent of the presence of pathogens.

Elevated IL-6 is a pathway that associates periodontitis with an established systemic risk factor, Diabetes[146], and a path of association with Coronary Heart Disease[147] and COPD[148]. Pre-existing circulating levels of IL-6 before and following the initial COVID infection, owing to its proinflammatory action and regulation of dendritic, B, and T cells[149] would favor LC. Conversely, LC may act as the initial trigger for systemic IL-6 elevation, resulting in damage to various tissues, including the periodontium.

6.2. A Persistent Active Immune Response to the SARS-CoV-2, the Key to LC

6.2.1. The Resolution of the SARS-Cov-2 Infection

Recovery from COVID-19 is common; however, an altered immune phenotype and/or function may persist in convalescent individuals[150,151,152,153]. Neutralizing antibody counts display a continuous decline correlated with the severity of the initial acute COVID-19 infection. Some individuals with a high peak infective viral load have maintained elevated neutralizing antibody titers afterward. In contrast, individuals with lower loads have experienced a gradual decline, returning to baseline levels even more than three months after disease onset[94].

An example of persistent immune response is among elderly individuals who survive severe COVID-19 disease and experience a late increase in circulating CD4+, CD8+, and double-negative B cell populations. Over time, this is characterized by improvements in dysfunctional T and B cells (including alterations in cell memory) and increased frequencies of cell activation and exhaustion, which contrast with the depletion observed during the acute phase[67,74,150,154,155,156].

LC is associated with persistent immunological dysregulation and can affect individuals with initial asymptomatic responses and those with mild, moderate, or severe cases[154,157,158,159,160,161,162,163]. Diminished numbers of DCs, can be detected even seven months post-SARS-CoV-2 infection[73], with continuous neutrophil activity, persistent inflammatory cytokine production, and deficient naive T and B cell numbers[154,155].

Periodontitis is characterized by ongoing elevated neutrophil activity and the production of inflammatory cytokines. In alignment with the continuous activity of neutrophils and persistent inflammatory cytokine production observed in LC, an imbalanced and dysregulated recruitment of neutrophils may occur at periodontal sites due to overwhelming microbial challenges[102,164].

However, the dysregulation observed in periodontitis may lead to an increase in cells that will have a reduced count in LC, such as T cells, B cells, natural killer (NK) cells, macrophages, and DCs, all of which may contribute to the initiation and exacerbation of periodontitis[164,165,166]. The activation and proliferation of these cells will further perpetuate proinflammatory cytokine production.

6.2.2. A Persistent Dysregulation of T-Cells in LC

The behavior of T-cells after the initial COVID infection is likely to be one of the main factors that result in LC. However, the findings regarding these cells are inconsistent. In some cases, a short life cycle of cytotoxic CD8+ was observed[167], and a more significant signal toward cell death from T-cells than the antigenic memory[168]. However, other studies with subjects with areas of persistent SARS-CoV-2 infection, like the lungs, will have larger counts of circulating specific CD8+ T-cells with increased production of IFN Gamma, TNF, IL-6, and C-reactive protein[169]. Similar patients have exhibited dysregulation of tissue-resident CD8+ T-cells from lung biopsies[170].

6.2.3. A Broad and Continuous Adaptive Immune Response Is Part of LC

Although most patients recovering from acute COVID will show a reduced count of antibody-secreting B-cells during this stage, a small percentage will maintain elevated counts of these cells[171]. In line with this finding, LC is characterized by broad adaptive immune activation, with B-cells resuming the production of antibodies against past infections, alongside an increase in CD4+ and CD8+ specific lineages targeting SARS-CoV-2 and cytomegalovirus during convalescence[172]. Other viral infections may (re) emerge during COVID-19, with the Epstein-Barr virus (EBV) relevantly documented in the literature. This co-infection is considered a potential factor for LC and is linked to neurocognitive symptoms such as fatigue[173].

EBV is one of the Herpesviruses associated with periodontitis, similar to Cytomegalovirus. Traditionally, EBV is an etiologic factor for Hairy Leukoplakia, classically regarded as a pathognomonic indicator of HIV infection, but it is not limited to this[174] and is also associated with some oral cancers[175]. EBV is linked to periodontitis in populations across Asia, Europe, and America. It can be detected in subgingival plaque and GCF, showing a positive correlation between the presence of EBV, gingival inflammation, and probing depths[176]. Active periodontitis can act as a reservoir for EBV, which may co-infect with SARS-CoV-2 and is considered a precursor for LC.

Another way the adaptive immune system sustains activity in LC is through COVID-driven autoimmunity. This phenomenon occurs even during the acute phase. It aims to neutralize IFN type I via autoantibodies against it[177,178,179], resulting in a reduced IFN response, failed SARS-CoV-2 clearance, and ongoing local and systemic inflammation[68,70,72,180,181,182,183]. Reports of autoantibodies against other cytokines, chemokines, cell-surface proteins[184], and phospholipids [185] have all been noted.

In LC, autoantibody production is continuous due to the still active adaptive immunity via double-negative B cells, even in subjects with mild initial COVID[171,186]. This pattern resembles several autoimmune diseases, as it involves autoantibodies against components of connective tissue, cytokines, chemokines, and antinuclear antibodies[187]. The co-infection of EBV with SARS-CoV-2 may also contribute to the autoimmunity associated with LC, supported by scientific evidence showing that EBV alone can lead to autoimmunity[188,189,190]. However, there is no consensus on whether COVID triggers autoimmune mechanisms or if these are genetically determined and predate the initial SARS-CoV-2 infection[177]. Furthermore, the ongoing activity of adaptive immunity does not necessarily mean that the autoimmunity process will continue. For instance, autoantibodies against IFN-I are not linked to LC[191].

The role of autoimmunity in LC remains unclear. Studies vary, with some demonstrating a correlation between autoantibodies and LC[192], while others do not[193]. Opinions differ on whether autoimmunity is a risk factor for LC[172], if LC is an autoimmune disease[194], or if autoantibodies could offer protection against LC[195]. There is no consensus on the issue.

6.3. The Complement System

The complement system, an integral part of innate immune regulation that plays a crucial role in immunity and homeostasis by targeting pathogens and damaged cells, has recently been implicated in the activation mechanisms of L[196]. Individuals with LC exhibit an imbalance in terminal complement complex (TCC) formation, which is characterized by elevated levels of soluble C5bC6 complexes, diminished concentrations of C7-containing TCC formations, and associated thrombo-inflammation. Current literature highlights increased markers of tissue injury, red blood cell lysis, platelet activation, and monocyte–platelet aggregates[196]. Active LC is characterized by sustained activation of specific alternative and classical complement pathways.

The complement system might be involved in periodontitis’ pathogenesis as well[197]. Complement proteins are activated in high quantities during active periodontitis, with their components and cleavage products found in the diseased gingival tissues, in contrast to being undetected or present in low levels in healthy gingival tissues. The complement components identified in the affected gingiva or GCF encompass the entire immune cascade, including C1q, factor B, Bb, C3, C3a, C3b, C3c, C3d, C4, C5, C5a, C5b, and C9. A single nucleotide polymorphism in the gene coding for complement C5 and C3 has been linked to periodontitis[198,199]. C3a and C5a, along with mast cells, are involved in osteoclastogenesis and alveolar bone loss[165].

6.4. The Role of IL-17, RANKL, and Matrix Metalloproteinases (MMPs) in Bone Metabolism Related to LC

In the context of LC, the potential direct effects of SARS-CoV-2 are associated with its entry through angiotensin-converting enzyme 2 (ACE-2) receptors on bone cells, including osteoclasts and osteoblasts, which may disrupt the bone remodeling process[200,201]. The heightened production of inflammatory cytokines, recruitment of Th17 cells, and alterations in RANKL and osteoprotegerin (OPG) signaling are among the proposed mechanisms linking COVID-19 to osteoporosis and bone loss observed in affected patients[201,202,203].

In animal models, cytokine storms characterized by elevated serum levels of IL-1β, IL-6, and TNF-α have been shown to lead to trabecular bone loss in long bones and lumbar vertebrae, worsening from the acute to the post-recovery phase in SARS-CoV-2 in hamsters[204]. Th17 cells promote osteoclastogenesis through IL-17-mediated induction of RANKL[205], and As noted, elevated Th17 cell and IL-17 levels have been observed in individuals with LC[201,203].

Consequently, due to the rise in inflammatory markers, increased expression of MMPs, such as MMP-1, 2, 3, 7, 8, and 9—has been noted in various pathophysiological processes, ranging from chronic fatigue symptoms to the rapid progression of pulmonary fibrosis. Specifically, MMP-1, 8, and 9 are significantly elevated levels correlated with disease severity and increased neutrophil degranulation, as well as endothelial function, metabolic dysfunction, and the development of pulmonary fibrosis, which are all integral to the pathophysiology of LC[206,207,208,209,210,211]. MMP-8, primarily secreted by neutrophils, is a major degrading enzyme for interstitial collagens in periodontitis[212,213]. Additionally, MMPs, including MMP-8 and 9, contribute to the severity of COVID-19 infections[214,215,216].

At the periodontal site level, CD4+ T cells (decreased in LC) in gingival tissue are the primary contributors to elevated receptor activator of nuclear factor kappa-B (NFκB) ligand (RANKL) levels in individuals with chronic periodontitis[166]. However, neutrophils can facilitate the progression of periodontitis by inducing the recruitment of Th17 cell-derived CD4+ T cells (elevated in LC), which are activated and differentiated by dendritic cells (DCs) [217,218]in active periodontitis[219], and by promoting the accumulation of B-cells and plasma cells in severe lesions[102].

More specifically, the IL-17 cytokine-derived Th17 cells produced in periodontal tissue [220,221] can stimulate macrophages and other cellular sources, such as endothelial cells, epithelial cells, and fibroblasts, to produce pro-inflammatory mediators (e.g., IL-6, IL-8, TNF-α, IL-1β, PGE2) with partial synergy with LC’s cytokine storm[102,212] and can direct osteoblasts to produce RANKL[222], resulting in bone resorption[212,223,224].

In addition to secreting IL-17, Th17 cells also express RANKL, which activates osteoclasts[225]. Thus, increased IL-17 levels during a COVID-19 infection can potentially enhance osteoclast activity and bone resorption in the development of periodontitis. IL-17 induces the expression of MMP in fibroblasts, leading to the destruction of periodontal connective tissue[91,102].

B cells' production of neutralizing antibodies may directly or indirectly contribute to the destruction of periodontal connective tissue or alveolar bone by expressing pro-inflammatory cytokines, MMPs, and RANKL[102,226,227].

The key immune-inflammatory components shared between LC and periodontitis are summarized in Table 1, highlighting similarities and differences in immune cell activity, cytokine production, and other mediators.

As illustrated in Figure 1, these overlapping mechanisms between initial COVID-19 and periodontitis involve interconnected viral, immune, and inflammatory pathways.

7. The Potential Mechanisms of COVID-19/LC Effects on Periodontitis

Mechanistic understanding of the potential impact of LC on periodontitis development/progression is needed. A recent scoping review suggests that periodontitis and COVID-19 may independently increase serum levels of IL-1β, IL-6, and TNF-α in the same individual[228]. However, it lacks information on the joint or causal effects between the two diseases[228]. As previously mentioned, the association between ‘sequelae’ from COVID-19 and periodontitis has been cross-sectionally assessed[37]. The reverse assessment in a case-control study of COVID-19 indicated an increased salivary IL-6 level measured at two time points in individuals with COVID-19 and periodontitis[229]. The researchers reported that periodontitis was associated with increased salivary levels of RANKL and IL-1β during and after COVID-19[229]. Another study demonstrated that individuals with acute COVID-19 subsequently had an increased serum RANKL/OPG ratio compared to healthy controls. It also showed that in vivo murine coronavirus (MHV-3) can induce an osteoporotic phenotype via TNF and on macrophage/osteoclast infection in a mouse model of SARS-like disease[230].

7.1. The Role of Angiotensin-Converting Enzyme 2 (ACE2) on the LC and Periodontitis Association

Another biological pathway linking LC with periodontitis involves the role of ACE2 cellular receptors, which are abundant in various human tissues[231]. ACE2 is central to the primary SARS-CoV-2 infection pathway for access to and invasion of several organs and tissues, primarily in conjunction with the co-receptor “Transmembrane protease serine 2” (TMPRSS2) in the upper respiratory epithelium[232,233,234,235]. Following initial infection, SARS-CoV-2 induces cells to overexpress ACE2 through 1) direct binding of its spike protein to the ACE2 receptor[236] or (as recently reported) 2) direct or indirect binding and activation of Toll-like receptor 4 (TLR4)[237], followed by fusion of the viral and host cell membranes, promoted by TMPRSS2 and furin molecules[236,238,239], resulting in replication, exacerbation, and persistent inflammation[237].

Both ACE2 and TMPRSS2 are present in the epithelial component of the gingiva, specifically in the sulcular and pocket epitheliums. ACE2 is localized in the nucleus and cytoplasm of the spinous-basal layer, while TMPRSS2 is detected in the gingival epithelium as well as the horny and spinous-basal layers, with its intracellular expression occurring in the cytoplasm and cell membrane[240].

Prior or ongoing infections of mucosal, epithelial, and endothelial cells — associated with inflammation in the respiratory, renal, vascular, gastrointestinal, or cardiac tissues — increase the expression of ACE2, making these tissues more susceptible to SARS-CoV-2 infection[241,242]. Cytokine-mediated tissue stimulation from COVID-19 or other inflammatory processes can upregulate ACE2 expression, potentially creating a positive feedback loop that enhances viral replication[243,244,245,246,247]. SARS-CoV-2 infections of the endothelium introduce the virus to various target organs[248], portraying COVID-19 as a vascular disease[249].

Thus, prolonged or latent chronic SARS-CoV-2 antigen exposure from ACE2-rich tissues could precipitate the immunological dysregulation observed in LC[154,250]. Higher titers of plasma ACE2 activity have been noted in individuals with LC for up to four months after the acute SARS-CoV-2 infection[250]. Similarly, SARS-CoV-2 RNA and/or proteins have been detected long after the acute SARS-CoV-2 infection in gastrointestinal organ tissues, including the stomach, colon, intestine, appendix, gut mucosa, epithelium, and colorectal lamina propria, as well as in other tissues, such as skin, breasts, gallbladder, and olfactory neuroepithelium. Additionally, SARS-CoV-2 viral particles have been identified in the stool and blood of LC patients[251]. The presence of viral RNA in the plasma[172] and the persistence of the virus in “immunologic sanctuaries” like the gastrointestinal tract, olfactory system, and brain[252,253] are regarded as factors that may predict LC. However, when long-term SARS-CoV-2 antigen shedding is the primary subject of cross-sectional epidemiologic studies, associations with LC differ by site. No correlation was found between salivary long shedding and LC[167] or the gastrointestinal tract[252]. However, a connection was noted between SARS-CoV-2 in the olfactory mucosa and local LC symptoms[254].

Evidence of SARS-CoV-2 presence in the oral cavity during LC is still limited. SARS-CoV-2 was found in subsequent tissue biopsies of fungiform papillae from patients with LC sequelae[255]. SARS-CoV-2 has been detected in the supragingival and subgingival biofilms of individuals with acute COVID-19, even those without periodontitis[256], and in the saliva of individuals with asymptomatic or mild COVID-19[257]. Similarly, ACE2 activity in saliva correlates with an individual’s susceptibility to SARS-CoV-2 infection and disease severity[258]. The epithelial cells of the oral mucosa, tongue, and salivary glands exhibit higher ACE2 expression; these cells may serve as initial and late sites for SARS-CoV-2 infection[50,259].

Moreover, similar to other viral infections, e.g., herpesviruses[260,261], periodontal pockets with ulcerated gingival epithelium, exposed connective tissue, and periodontal ligament cells expressing higher levels of ACE2[240] could serve as reservoirs for the SARS-CoV-2 virus[262]. The presence of the virus in these periodontal pockets could exacerbate infections in both periodontal and systemic contexts.

7.2. LC May Affect Oral Dysbiosis, Increasing Susceptibility to Chronic Infections, Including Periodontitis

Persistent immune dysregulation caused by LC creates an optimal environment for an excessive response to other chronic infections. Gut dysbiosis leading to long-term digestive complications has been reported in individuals with acute SARS-CoV-2 infection or L[263,264,265]. More specifically, SARS-CoV-2 RNA was detected in patients’ stool samples ten months after the acute phase of COVID-19, and fecal viral RNA shedding was linked to gastrointestinal symptoms in individuals with L[253]. Similar findings have been noted in recent literature[265,266], suggesting a prolonged and possibly permanent viral presence in fecal material[267].

Moreover, recent findings suggest that the posterior segment of the oropharyngeal microbiome may act as a reservoir for bacteria associated with pneumonia and chronic lung infections in SARS-CoV-2 cases. COVID-19 infection can induce oropharyngeal dysbiosis, which may persist for at least 30 days, regardless of viral clearance or antibiotic treatment[268].

The link between periodontal pathogens and LC remains unclear. Bemquerer et al. (2024) reported no significant changes in subgingival pathogens when examining periodontitis in acute COVID-199[229], whereas Haran et al. (2021), in their longitudinal study, found that higher early levels of Prevotella and Veillonella in acute COVID-19 patients were associated with prolonged symptoms, ultimately leading to LC[269]. Conversely, there have been no assessments regarding the potential effects of chronic LC on subgingival microbial symbiosis that could contribute to periodontitis development.

Figure 2 illustrates the possible bidirectional pathways connecting LC and periodontitis, emphasizing chronic inflammatory feedback loops.

8. Summary

LC, an emerging new disease, can persist after the acute phase of COVID-19. Like diabetes, the immuno-inflammatory dysregulation associated with LC may increase susceptibility to periodontitis, making individuals with this disease a previously untargeted population of interest for preventing and treating periodontitis. Although the epidemiological connection between these two chronic conditions requires further investigation, it is plausible that the onset of periodontitis in previously healthy individuals or the worsening of existing periodontitis in those with a history may represent an oral manifestation of LC.

LC exerts a global pro-inflammatory influence across multiple facets of the immune system, characterized by sustained increases in neutrophils, production of pro-inflammatory cytokines, and activation of immune cells, alongside elevated levels of RANKL, MMPs, and complement factors- features that are common in both periodontitis and LC.

LC can drive gut dysbiosis and may also cause dysbiosis of the oral microbiome, increasing susceptibility to periodontitis through subgingival dysbiosis. While evidence of SARS-CoV-2 presence in the oral cavity related to LC remains limited, the gingiva and periodontal ligament cells in periodontal pockets show increased ACE2 expression, suggesting that areas with active periodontitis may serve as reservoirs for SARS-CoV-2. However, further epidemiological, tissue, cell, and molecular studies confirming a population relationship will be necessary to clarify the mechanisms linking LC and periodontitis.

Further clinical investigations are essential to enhance our understanding of the mechanisms linking LC and periodontitis. By elucidating the connections between chronic comorbid conditions (e.g., diabetes, cardiovascular disease, obesity) and their relationships with COVID-19 or LC, as well as periodontitis, we can focus on preventing and treating periodontitis. This approach may yield dual benefits for both oral health and overall health in individuals with LC. Public educational initiatives about the potential impacts of LC on oral and general health are needed to raise awareness of the possible development of periodontitis and other adverse events associated with LC, such as cardiovascular disease.