8.1 Periodontal disease and its relationship with COVID-19

Periodontal disease is characterized by progressive inflammation and destruction of periodontal tissues owing to the colonization by periodontopathogens. Moreover, this can lead to tooth loss and masticatory dysfunction in adults. The prevalence of periodontal disease increases with increasing age, with 70% of adults above 65 years of age experiencing periodontitis in the United States (Eke et al., 2016). Microbial dysbiosis has been identified in the pathogenesis of periodontitis. This dysfunction triggers a host immune defense against pathogenic bacteria through the stimulation of proinflammatory cytokines and cytokine-mediated involvement of neutrophils at the site of infection (Pan et al., 2019). Periodontal bacteria have the potential to invade and populate other distant organs, and systemic dissemination is facilitated by damaging the gingival epithelial barrier and spreading through the bloodstream (Aquino-Martinez & Hernandez-Vigueras, 2021). Moreover, following translocation into the lower respiratory tract via the oral–lung aspiration axis, these bacteria might aggravate SARS-CoV-2-induced severe lung infections by elevating the secretion of inflammatory cytokines, including interleukin-6 (IL-6).

Additionally, current research has established a link between oral microbiota and periodontal inflammation (Van Dyke et al., 2020). The primary role is played by the inflammatory continuum, followed by microbial specificity (pathogenicity). This concept is also consistent with the most recent periodontal disease classification (Caton et al., 2018), which now focuses on how the resolution of inflammation brings a change in microbial composition and restoration of microbiological homeostasis.

In addition, saliva appears to be another easy mode of transmission for COVID-19, either via infected persons' nasal secretions, microdroplets, or coughs or via inhalation of salivary droplets into their own lower respiratory tract (Carrouel et al., 2021). However, this aspiration axis may not always promote the spread of harmful bacteria; rather, proinflammatory cytokines generated during periodontal inflammation disseminate into the circulation and contribute to the development of systemic diseases such as COVID-19. Table 2 lists significant developments associated with periodontitis and COVID-19.

8.2 Periodontal bacteria-induced senescence driving SARS-CoV-2 invasion

Periodontal bacterial infection in the oral cavity accelerates senescence in distant organs through the oral–lung aspiration axis or inhalation of saliva. The most frequently implicated cells include lung epithelial, adipocyte precursor, and microglial cells. Prolonged contact with lipopolysaccharide (LPS), a component of Porphyromonas gingivalis cell wall, initiates cellular senescence followed by the recruitment of neutrophils, pro-inflammatory cytokines, and phagocytic cells. Additionally, P. gingivalis-induced periodontal inflammation stimulates the formation of reactive oxygen species (ROS), which results in the initiation and stabilization of DNA damage. As a result of increased ROS formation, the LPS-induced oxidative stress results in DNA damage and the expression of pro-and antiapoptotic proteins such as Bcl2.

These cascades of cellular reactions result in cell growth arrest due to the elevated expression of senescence-associated β-galactosidase, increased p53 levels, and enlarged cytoplasm undergoing apoptosis. Additionally, nuclear DNA damage has been associated with enhanced proinflammatory responses and innate immune activation, further propagating cellular senescence in the context of periodontal inflammation (Aquino-Martinez et al., 2020). Incidentally, induced DNA damage results in dysfunctional cells in the pulmonary epithelium and degradation in the local microenvironment by increasing the expression of the transmembrane proteins vimentin and ACE2, which are required to facilitate an enhanced SARS-CoV-2 entry and viral replication (Aquino-Martinez et al., 2020; Kim et al., 2016). Vimentin, a cytoskeletal filamentous protein that is highly expressed in senescent cells, acts as a coreceptor in addition to ACE2, contributing to the increased SARS-CoV-2 attachment to lung epithelial cells as ACE2 alone cannot drive efficient viral binding and entry (Yu et al., 2016).

8.3 Oral microbiota and influence on human lung diseases

The oral cavity houses the second highest number of microbes in the human body, including bacteria, archaea, fungi, and viruses. Previous studies examining microbial DNA from the calculus of ancient human remains have identified antibiotic-resistant genes in opportunistic pathogens of the oral cavity (Warinner et al., 2014). These observations suggest that the oral cavity potentially acts as an ecological reservoir for several pathogens, subsequently triggering a set of local and systemic diseases. The main bacterial genera Streptococcus, Prevotella, Neisseria, Corynebacterium, Leptotrichia, Veillonella, Fusobacterium, and Capnocytophaga are abundant in the oral cavity. In contrast, healthy lungs are predominated by Streptococcus, Fusobacterium, Pseudomonas, Veillonella, Prevotella, and Capnocytophaga, which also colonize the oral cavity of healthy humans (Wypych et al., 2019).

Patients with ventilator-assisted pneumonia (VAP) demonstrate the oropharyngeal colonization of pathogens underlying the pathophysiological mechanism behind VAP development (Bao et al., 2020). Further studies have provided evidence on bacterial pathogens (Streptococcus oralis, Prevotella salivae, and Mycoplasma salivarium) that populate the respiratory tract of healthy individuals asymptomatically, or predominating acellular bronchoalveolar lavage fluid of healthy individuals and patients with VAP, as identified by 16S rRNA gene sequencing (Bahrani-Mougeot et al., 2007; Y. Li et al., 2019; Venkataraman et al., 2015). Periodontal microbes are also involved in the development of aspiration pneumonia (Ellen, 1992). Disruption of the oral microbiome has been shown to cause the dissemination of periodontal bacteria into the lungs and exacerbate existing systemic diseases (Jepsen et al., 2015; McCulloch et al., 2017). Moreover, the accumulation of senescent cells generated by aging, chronic inflammation, smoking, and bacterial infection accelerates the onset of these systemic diseases by attenuating tissue regeneration through stimulation and proinflammatory cytokines (Aquino-Martinez et al., 2020). The oral cavity contains ACE2 receptors on all mucosal surfaces, particularly on the dorsum of the tongue; therefore, they could facilitate an entry into the cells of the SARS-2 virus. Moreover, the periodontal sulcus or pocket functions as a reservoir for SARS-2 (Xiang et al., 2020). This is particularly important in the case of the new Omicron variant because of its preference for the upper respiratory tract over the lungs/lower respiratory tract. Another important aspect is the role of salivary glands as reservoirs for the SARS-2 virus. The virus found in saliva arises not only from the oral cavity/periodontal pockets but also from the salivary glands (J. Xu, Li, et al., 2020).

8.4 Lung inflammation and cytokine connection to SARS-CoV-2

The invasion of SARS-CoV-2 is mediated by the adherence to ACE2 receptors through the enzymatic cleavage of the SARS-CoV-2 spike protein involving furin-TMPRSS2-elastase, which is located on the host cell surface (Bestle et al., 2020; J. Wang, Jiang, et al., 2020). According to previous studies, ACE2 is highly expressed in type II alveolar epithelial cells, indicating that these cells serve as the primary targets for the viral attack, with 83% of cells positively stained for ACE2 receptors (Zhao et al., 2020). In the presence of oxidative stress and severe inflammation, ACE2 acts as an anti-inflammatory and antioxidant factor, contributing to the protection and maintenance of cellular integrity by inhibiting the nuclear factor-κB pathway (Fang et al., 2019). However, the entry of SARS-CoV-2 into the host cells, which is facilitated by the viral spike protein causes the virus–receptor complex internalization and ACE2 downregulation in infected cells (Zhang et al., 2020). As a result, the NF-κB pathway is triggered, leading to p38/MAPK activation and an elevated level of cytokine release, including IL-6 and tumor necrosis factor-α (TNF-α) (Bouhaddou et al., 2020; Fang et al., 2019; Hirano & Murakami, 2020).

Moreover, microbial pathogens and nuclear DNA damage converge to activate NF-κB, mediated by Toll-like receptor 4 and ataxia telangiectasia mutated, which primarily sense double-stranded DNA breaks within the nucleus (Aquino-Martinez et al., 2020). Activated p38 is involved in cell growth arrest and promotes cellular senescence by influencing the senescence-stimulating factors. Moreover, its inhibition by SB203580 is associated with a delayed onset of senescence. It has been speculated that the accumulation of P. gingivalis-derived LPS exacerbated the senescence in lung tissues, which increased the likelihood of precipitating a greater level of SARS-CoV-2 infection and enhancing viral replication (Kim et al., 2016). However, further investigation is required to validate this hypothesis.

Previous experiments demonstrating a relationship between a healthy oral microbiome and the development of systemic diseases, including COVID-19, have attempted to elucidate the association between periodontitis and COVID-19. In particular, P. gingivalis increases its virulence by evading the host immune surveillance through the delayed infiltration of neutrophils and inhibition of IL-8 secretion at the site of infection (Darveau et al., 1998). The lack of IL-8 is associated with the overgrowth of these pathogens and increased SARS-CoV-2 invasion because of the disrupted cellular integrity in the pulmonary alveolar epithelial lining. Elevated cytokine levels further accelerate this disruption by disseminating periodontopathogens to the oral cavity and lungs. Consequently, a high expression profile involving proinflammatory cytokines, IL-1, IL-7, IL-10, IL-17, IL-8, TNF-α, and monocyte chemoattractant protein-1, were detected both in patients with periodontitis and those with COVID-19 (Sahni & Gupta, 2020) (Figure 1). In addition, IL-17 has been identified as a senescence stimulant that exacerbates lung inflammation and could serve as a plausible biomarker for COVID-19. These observations confirmed that the cytokines disseminated to other distant organs, including the lungs, through the bloodstream or oral-lung aspiration axis, induce damage to the lung epithelial lining, and create favorable conditions for severe SARS-CoV-2 infection.

8.5 T-cell responses against periodontitis and its connection with COVID-19

Regulatory T cells (T-regs) and T helper (Th) cells protect against bacterial infection and periodontal invasion in the lungs. According to previous research, bacteria and their metabolites, such as LPS and short-chain fatty acids translocated from the oral cavity into the lungs, contribute to the development of the T-reg response. Previous exposure to periodontopathogens (Prevotella sp.) and their metabolites are associated with the inhibited production of interferon-γ and IL-17A, which confer higher susceptibility to tuberculosis and other respiratory diseases, including severe COVID-19 disease (Segal et al., 2017). A study involving 1099 patients in China demonstrated that patients with severe COVID-19 presented with peripheral lymphocytopenia and hyperactivated CD4+ and CD8+ T cells. A dysregulated T-cell response is accelerated by elevated proinflammatory CCR6+ Th17 in CD4+ T cells and a high concentration of cytotoxic granules in CD8+ T cells. These observations suggest that, in addition to chronic periodontal inflammation, hyperactivated and reduced levels of CD4+ and CD8+ T cells are implicated in immune injury and the onset of cytokine storm in the lungs and other vital organs of patients with COVID-19, which are associated with severe COVID-19 cases, COVID-19-induced pneumonia, and death.

8.6 Host factors and periodontal therapy

Middle-aged and older adults with periodontitis and other comorbidities, or those harboring an unhealthy oral microbiome with impaired immune functions, are more susceptible to SARS-CoV-2 infection and its associated complications, even after eliminating the virus from the system (Chen et al., 2020). Cancer malignancies, chronic obstructive pulmonary disease, diabetes, and hypertension appear to be driving factors for promoting viral entry and evasion of host immune defense, leading to severe disease progression and eventually death (Guan et al., 2020). Since microbial dysbiosis, bacterial superinfection, and host hyperresponsiveness play vital roles in the severity of COVID-19, emphasis should be placed on periodontal maintenance (Sukumar & Tadepalli, 2021). Interestingly, evidence indicates a potential role of Galectin-3 mediated increased immune response and increased viral attachment in the association between periodontal disease and COVID-19. Moreover, an area in the coronavirus spike protein depicts a morphology that is highly similar to that of Galectin-3. Therefore, the maintenance of a healthy periodontal status appears critical in SARS-CoV-2 infection for control during the COVID-19 pandemic (Kara et al., 2020; Larvin et al., 2020).

In addition, a strong correlation between the severity of COVID-19 and type 2 diabetes in patients with periodontitis was recently reported, showing that the number of ACE2 receptors was prominently higher in those with periodontal disease and diabetes than in those with periodontal disease alone (Casillas Santana et al., 2021). In other words, diabetes and periodontal disease significantly contributed to the increase in the number of ACE2 receptors among individuals, thereby enhancing the susceptibility to SARS-CoV-2 infection and subsequently accelerating the disease prognosis. However, further clinical studies are needed to explore whether patients with COVID-19 might benefit from periodontal treatment, as it could reduce the severity of complications (Shamsoddin, 2021).