Cells displaying senescence-like features may facilitate cell entry and promote efficient coronavirus replication. Prolonged exposure to LPS causes accelerated senescence in different cell types, including adipocyte precursors [122], microglial cells [123], and pulmonary epithelial cells [124]. Recent evidence indicates that cells can undergo DNA damage-driven cellular senescence as result of repeated exposure to P. gingivalis LPS [125,126]. Although it is recognized that senescent cells contribute to deteriorating their local environment, these dysfunctional cells could also facilitate pathogen infection. Shivshankar et al. demonstrated that senescent cells promote bacterial adhesion to lung cells, eventually resulting in increased susceptibility to bacterial-induced pneumonia in older adults [127]. On the other hand, given that the entry of SARS-CoV-2 in host cells depends on the attachment to specific cell receptors, senescent cells may contribute to facilitating this process.

Vimentin is highly expressed in senescent cells. This filamentous cytoskeletal protein promotes the typical enlarged senescent morphology and plays an essential role in coronavirus cell binding and entry [128,129]. Yu et al. demonstrated that vimentin directly interacts with the spike protein of the coronavirus and that the susceptibility of coronavirus infection is notably reduced by eliminating vimentin activity [129]. Considering that ACE2 expression alone is not sufficient for viral infection, vimentin might act as a surface coreceptor for coronavirus, and likely for SARS-CoV-2 infection as well [129,130,131]. As consequence of this idea, it has been proposed that decreasing vimentin expression could be an attractive strategy for the treatment of COVID-19 infection [131]. Interestingly, Kara et al. recently reported that the strong relationship between severe periodontal disease and COVID-19 could be explained through increased viral attachment and immune response mediated by galectin-3 [132]. Galactin-3 has been identified in the cytoplasm of senescent human fibroblasts, indicating that cells that undergo proliferative arrest lack factors required for the nuclear import of this protein [133]. Furthermore, galectin-3 is highly secreted by senescent mesenchymal stem cells, which could promote the growth of colorectal cancer cells [134]. Consistent with the role of vimentin mentioned above, increased galectin-3 expression by senescent cells could facilitate SARS-CoV-2 attachment and cell entry. Of note, Diaz-Alvarez and Ortega reported that galectin-3 directly binds to invading pathogens and contributes to the immune system reaction against infection [135]. Indeed, galectin-3 is rapidly upregulated in gastric epithelial cells in response to Helicobacter pylori, which through the expression of CagA, promotes cellular senescence in human gastric epithelial cells and extra-gastric cells [136,137].

Importantly, Bouhaddou et al. demonstrated that SARS-CoV-2 cell infection promotes the production of several cytokines, cell growth arrest, and p38 MAPK activation. These authors also identified that following SARS-CoV-2 infection, an upregulated IL-6 and TNF-α expression is observed, which was inhibited by SB203580 (a p38 inhibitor). Intriguingly, SARS-CoV-2 replication was also decreased by p38 inhibition [66]. P38 MAPK is a key regulatory pathway implicated in cell growth arrest and modulates the expression of most senescence-associated factors. Consequently, p38 inhibition delays the onset of senescence [138,139]. In agreement with the concept that viruses may use senescent cells to enhance replication, Kim et al. found that primary human bronchial epithelial cells that undergo replicative senescence were more susceptible to viral infection and enhanced replication than nonsenescent cells [140]. Therefore, we speculate that age-related accumulation of senescent cells in lung tissues is aggravated by P. gingivalis LPS (and other Gram-negative bacteria that colonize lung tissues), which facilitates SARS-CoV-2 cell binding, entry, and more efficient viral replication. However, additional studies are required to validate this idea (Figure 3).

ACE2 is crucial for SARS-CoV-2 cell binding and replication, but it also plays an essential role in protecting lung tissues from excessive inflammation. Whereas ACE2 mRNA is expressed in practically all human organs, the tissue distribution of ACE2 protein levels seems to be more restricted. Positive staining for ACE2 has been identified in specific sites of certain organs. For instance, in normal lungs, strong immunostaining for ACE2 is observed in alveolar epithelial cells [141]. In agreement with this, Zhao et al. demonstrated that 83% of cells expressing ACE2 in the lung are type II alveolar epithelial cells, suggesting that these cells can have an important role during SARS-CoV-2 infection [142]. In addition to mediating SARS-CoV-2 cell entry, ACE2 acts as an anti-inflammatory and antioxidant factor. Previous studies have demonstrated that ACE2 has a protective function against oxidative stress and severe inflammatory reactions, in part by inhibiting the NF-kB pathway [143,144,145]. Intriguingly, SARS-CoV—and probably SARS-CoV-2—spike protein binding results in ACE2 downregulation in the lungs of mice [146,147]. Along the same line, SARS-CoV-2 activates NF-kB, leading to cytokine secretion, including IL-6 and TNF-α [85]. Therefore, ACE2 expression is reduced after the attachment of the coronavirus spike in host cells, which results in the excessive secretion of key proinflammatory cytokines as a consequence of NF-kB upregulation.

Consistent with this protective role through the inhibition of NF-kB activity, ACE2 prevents both LPS-induced acute respiratory distress syndrome (ARDS) in a murine model and inflammatory injury in pulmonary microvascular endothelial cells [148,149]. Furthermore, ACE2 significantly decrease LPS-promoted IL-6 secretion by 75.6% and IL-1β by 86.7% in lung alveolar epithelial cells in vitro [150]. In addition, ACE2 protects mice from severe acute lung injury and failure induced by acid aspiration [151]. These studies suggest that ACE2 could defend lung tissues from LPS’s detrimental effects. A key finding was recently reported by Petruk et al.: they demonstrated the interaction between the SARS-CoV-2 spike and LPS from Escherichia coli and Pseudomonas aeruginosa, a Gram-negative bacteria found in the intestines and an opportunistic pathogen implicated in the etiology of ventilator-associated pneumonia (VAP), respectively [152]. More specifically, the SARS-CoV-2 spike protein can interact with lipid A, a component of LPS, and result in significant upregulation of the inflammatory reaction compared with the individual effect of LPS. Moreover, these authors found that the combination of the spike protein and low levels of LPS potentiates NF-kB activation. In addition to decreasing inflammation, ACE2 also could protect lung tissues from LPS-induced oxidative stress. Kim et al. reported that sublethal concentrations of LPS promote the formation of hydrogen peroxide (H₂O₂) in a dose-dependent manner in lung alveolar epithelial cells [124]. Consistent with this, acute lung injury induced by LPS is characterized by inflammatory damage and decreased ACE2 expression [153]. On the other hand, Sahni et al. recently proposed that the connection between periodontitis and COVID-19 could be through a common proinflammatory cytokine expression profile; that is, patients with severe symptoms of COVID-19 have increased serum IL-1β, IL-7, IL-10, IL-17, IL-8, TNF-α, and MCP-1 levels, among others [154]. The secretion of many of these cytokines is increased in periodontal tissues of patients with periodontal disease compared to healthy controls. For instance, IL-17 seems to play an important role in exacerbating lung inflammation, and this proinflammatory cytokine can serve as a biomarker of COVID-19 severity [155]. Of note, IL-17 plays an important role in periodontal disease pathogenesis, and it is secreted by senescent alveolar bone osteocytes [125,156]. Altogether, pre-existing Gram-negative bacterial infection and the associated presence of LPS might exacerbate local lung inflammation as result of SARS-CoV-2 spike protein binding by enhancing NF-kB activation.

Manipulation of the host immune defense by periodontal bacteria mediates the onset of inflammatory conditions locally, but also at distant organs colonized by those pathogens [157]. Although P. gingivalis displays an arsenal of virulence factors, its long-term persistence in invaded tissues depends on its ability to evade immune surveillance. During the early stages of invasion, P. gingivalis can delay the recruitment of neutrophils by inhibiting the expression of IL-8, a key chemokine that guides these immune cells into the site of infection. This absence of an IL-8 gradient severely affects local immune defense and promotes the overgrowth of these pathogens. This mechanism is called local chemokine paralysis [158]. However, periodontal pathogens are “inflammophilic” and they depend on inflammation for source nutrients. For that reason, once pathogenic bacteria increase in number and form a biofilm, they “proactively induce inflammation” [159,160].

P. gingivalis is also able to invade and survive intracellularly in different cell types, including vascular and epithelial cells in vitro and in vivo [158,161,162]. These pathogens inside epithelial cells may be protected from antibiotics [163]. Interestingly, the ability to decrease immune recognition is not an exclusive feature of P. gingivalis. For instance, T. forsythia, another pathogen implicated in periodontal disease etiology, can attenuate immune mechanisms of detection, leading to delayed bacterial elimination [164]. Another example is A. actinomycetemcomitans, which is recognized by its immunosuppressive properties [165,166]. Considering that with advancing aging, the host immune surveillance is impaired [167,168], these studies suggest that bacterial mechanisms of immune evasion can not only promote their overgrowth, but also facilitate SARS-CoV-2 replication in lung cells.