Streptococcus mutans is classified into four serotypes (c, e, f, and k) based on the composition and structure of the cell wall-associated rhamnose polysaccharides. Serotype c is predominant in the oral cavity, with a detection rate of over 70% in the mouths of healthy subjects; serotype e constitutes approximately 20%, and serotype k constitutes less than 5% (Nakano et al., 2004; Nakano et al., 2007c).

In systemic diseases, RGP contributes to the resistance of S. mutans against phagocytosis by human polymorphonuclear leukocytes (Tsuda et al., 2000), and is capable of binding to fibronectin, type I collagen, and laminin. This enables it to aggregate at the endocardium, thereby enhancing the virulence of infectious endocarditis (IE) strains. In the IE rat model, the virulence level of the strain containing intact RGP is significantly higher than that of the RGP- mutant, and RGP can trigger platelet aggregation, which may result in vascular stenosis at the site of S. mutans aggregation (Nagata et al., 2006). Additionally, the glucose side chains also exert varying degrees of influence on pathogenicity. For instance, the serotype k strain of Streptococcus with a defective glucose side chain has been demonstrated to be less prone to phagocytosis by polymorphonuclear leukocytes, leading to prolonged bacteremia.

Glucosyltransferases have been implicated in sucrose-dependent adhesion of S. mutans to tooth surfaces. S. mutans strains produce up to three glycosyltransferases, Gtf-B, -C, and -D. From infected heart valve tissue, S. mutans strains lacking expression of each of the three GTFs could be isolated (Munro and Macrina, 1993; Nomura et al., 2006). Mice infected with isogenic mutant strains lacking all three GTFs had significantly reduced survival (Shun et al., 2005). Nucleotides with high homology to erythromycin and macromycin resistance genes were found in the gtfB and gtfD genes respectively. The insertion of these resistance genes resulted in loss of GTFs expression and acquisition of bacterial resistance, possibly contributing to the high virulence of the strains against cardiovascular diseases (Nemoto et al., 2008).

GBPs, owing to their glucan-binding attributes, constitute significant virulence factors in dental caries, jointly functioning with GTFs to facilitate caries. However, within the bloodstream, only a deficiency in GBPs has been discovered to extend the duration of S. mutans bacteremia (Nomura et al., 2004).

In the oral cavity, this structurally complex, multifunctional adhesin mediates bacterial attachment to the salivary membrane of teeth through interactions with host scavenger receptors glycoprotein gp340 or protein DMBT-1 (Brady et al., 2010). In a rat bacteremia model, PA- S. mutants showed the strongest resistance to phagocytosis, exhibited stronger cell hydrophobicity, significantly prolonged the duration of bacteremia, and had significantly higher inflammatory markers than rats infected with the parental strain (Nakano et al., 2006b; Nakano et al., 2008; Matsumoto-Nakano et al., 2009).

Collagen-binding proteins primarily consists of Cnm and Cbm, and CBP + S. mutans is more commonly isolated from dental plaque of patients with bacteremia and infective endocarditis. Approximately 15% of S. mutans isolates contain Cnm, while Cbm is rarely detected (Abranches et al., 2011; Nomura et al., 2012). The genes encoding CBPs are not uniformly distributed among serotypes and are mainly concentrated in strains e, f, and k (Lapirattanakul et al., 2011).

Cnm is a 120 kDa protein encoded by the cnm gene (Sato et al., 2004), which is found in 10–20% of oral bacterial strains and is most commonly found in serotypes f and k (Nakano et al., 2007a; Nomura et al., 2009). Because Cnm can also bind to type I collagen and laminin, it may produce similar effects to RGP. Therefore, Cnm is highly associated with bacterial attachment to blood vessels, and studies have shown that Cnm is a necessary condition for S. mutans to invade endothelial cells and subsequently cause cardiovascular disease.

Cbm is another CBP that is encoded by the cbm gene. Its hypothesized collagen-binding domain has 80% identity and 90% similarity with the homologous region of Cnm. Cbm is found in less than 3% of oral strains, most commonly in serotype k, where most lack PA expression (Nomura et al., 2012; Nomura et al., 2013). The type I collagen binding level of Cbm is higher than that of Cnm and can bind fibrinogen. Nomura et al. (2014) found that in the presence of fibrinogen, Cbm + /PA- strains had higher platelet aggregation induction and fibrinogen binding activity than Cbm- mutants. In the absence of fibrinogen, the platelet aggregation induction activity of Cbm + strains was relatively weak, as most CBP + S. mutans cells have a negative charge on their surface, which inhibits the aggregation of similarly charged platelets (Nakano et al., 2011). Therefore, for Cbm + mutant Streptococcus, the presence of fibrinogen is essential, and it may act as a bridge molecule to allow Cbm + mutant Streptococcus to bind to platelets.

Fibronectin-binding proteins are cell envelope-associated proteins of S. mutans, including AtlA, RgpG, BrpA, and Psr (Lemos et al., 2019). Fibronectin-binding proteins mediate specific adhesion of S. mutans to fibronectin and endothelial cells (Chia et al., 2000). For instance, BrpA- S. mutants were more resistant to polymorphonuclear leukocyte phagocytosis and aggregation of platelets than the parental strain. The duration of bacteremia induced by this defective strain was longer in rats (Nakano et al., 2005).

The recently identified fibronectin-binding protein AtlA plays a role in S. mutans resistance to phagocytosis and survival in the bloodstream, and its deficiency results in reduced autolysin, prolonged chain length, and significantly reduced biofilm formation. Furthermore, physiological serum calcium concentrations promote its maturation. It is found to be associated with S. mutans survival and virulence to IE in a rat model (Jung et al., 2009).

In macrophages, S. mutans induces TNF-α and IL-1β production by activating signaling pathway ERK/p38/JNK and NF-κB through TLR2 (Toll-like receptor 2) and TLR4(Toll-like receptor 4), respectively (Kim et al., 2012). NF-êB activates a transcriptional response, leading to pro-IL-1β synthesis, and a second signaling pathway activates caspase-1-dependent IL-1β maturation and secretion via inflammasomes (Schroder and Tschopp, 2010).

TNF-α initiates a cytokine cascade and increases vascular permeability, recruiting macrophages and neutrophils to a site of infection. IL-1b is a cytokine produced mainly by activated mononuclear phagocytes, mediating host inflammatory responses in innate immunity. It has several biological effects, including phagocyte activation, antibody production, and T-cell polarization.

IL-6 and its soluble receptors are key mediators regulating neutrophils and monocytes recruitment (Kaplanski et al., 2003). One study showed GTFs didn’t promote infectivity without glucan but affected inflammation. In acute inflammation, GTFs were the main regulatory protein inducing IL-6 (Chia et al., 2001). GTFs may stimulate IL-6 during systemic infection in the spleen and surrounding vegetations (Chia et al., 2002). Clinical investigation showed serum IL-6 levels significantly increased in all endocarditis stages, while other cytokines didn’t significantly increase (Rawczynska-Englert et al., 2000; Alter et al., 2002). Therefore, sustained IL-6 activation may promote myocardial injury. Additionally, as a gram + bacterium, S. mutans collagen combined with adhesive matrix molecules can inhibit the classical complement pathway (Kang et al., 2013).

Streptococcus mutans can cause damage to various organs and systems after entering the blood. At present, the mechanism of research on cardiovascular system damage is relatively clear. CBPs can bind with type I collagen to damage blood vessels, and cause cardiovascular diseases such as cerebral hemorrhage and infectious endocarditis, as well as inflammatory bowel disease, IgA nephropathy and tumor metastasis.

In various clinical and animal studies, S. mutans is frequently detected in heart valve and atherosclerotic plaque samples, and its role in causing bacteremia and vascular damage has been observed (Lockhart et al., 2004; Nakano et al., 2006a; Nakano et al., 2007b; Nakano et al., 2009; Oliveira et al., 2015; Nomura et al., 2020a).

Compared to healthy subjects, the detection rate of non-serotype c strains, such as serotype k, is significantly higher in the heart valves of patients with cardiovascular disease. Due to changes in cell surface antigens of serotype k strains, including high-frequency loss of PA expression and GbpA (Glucan-binding protease A) expression, as well as reduced GbpC expression, these strains can resist leukocyte phagocytosis and survive for extended periods in the bloodstream (Nakano et al., 2002). Importantly, serotype k strains highly express Cnm or Cbm, which are critical virulence factors for adhesion to vascular endothelial cells and heart valves, contributing to cardiovascular disease.

IgAN is characterized by predominant IgA1 deposition in the mesangial region, with extracellular matrix proteins composed of type IV collagen, fibronectin, and more (Kokubo et al., 1998; Narita and Gejyo, 2008; Abrahamson et al., 2013). In IgA nephropathy, the relationship between tonsil immunity and glomerulonephritis has been established. However, certain pathogens may impact tonsil immunity, resulting in IgAN (Komatsu et al., 2008). Mucosal changes like infection can activate the innate immune system, exacerbate existing IgAN, and promote disease manifestations like hematuria (Floege and Feehally, 2016). Higher type IV collagen concentrations could promote more pronounced aggregation of S. mutans. Some reports suggest that S. mutans can induce severe nephritis involving the glomeruli, tubules in rabbits, as well as IgAN-like glomerulonephritis in rats (Albini et al., 1985; Naka et al., 2021). Cnm + S. mutans strains are associated with elevated urine protein and severe IgAN, while the Cnm protein itself has no direct effect on the kidneys (Misaki et al., 2016; Ito et al., 2019). Immune reactions with IgA in Cnm + mucosal tissue may lead to glycosylation defects in serum IgA1 molecules, with glycosylation defense in IgA1 molecules as the primary pathogenesis of IgAN (Tomana et al., 1999; Rodrigues et al., 2017). This plays an important role in IgAN pathogenesis.

Hotta et al. (2001) proposed tonsillectomy and steroid pulse therapy for IgAN patients can not only reduce hematuria/proteinuria but also improve remission rates. This may support the significance of tonsillectomy in IgAN patient treatment and the importance of oral care in preventing kidney disease.

”Two hit theory” is widely believed to be the mechanism for NASH development, where insulin resistance caused by metabolic syndrome from excessive nutrition leads to simple steatosis as the first hit. The second hit is oxidative stress, lipid peroxidation, and mitochondrial failure, accelerating liver inflammation and fibrosis, leading to NASH (Day and James, 1998). Compared to Cnm + /PA- variant S. mutans strain, Cnm + /PA + strain showed high virulence in aggravating NASH in mice (Naka et al., 2014; Naka et al., 2016). Cnm helps S. mutans adhere to liver cells without fatty acid accumulation. Cnm and PA may facilitate adhesion of S. mutans cells to hepatocytes without and with fatty acids, respectively. S. mutans expressing both PA and Cnm on the bacterial cell surface localizes in the liver and attaches to hepatocytes, leading to increased inflammatory cytokines related to oxidative stress, such as IFN-γ and metallothionein. This results in a second hit on liver cells, aggravating NASH (Naka et al., 2014). Increasing evidence supports clinical interaction between type IV collagen and Cnm + S. mutans.

Ulcerative colitis and Crohn’s disease are major inflammatory bowel diseases, which are chronic and recurrent intestinal diseases. Available data show that proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and immunosuppressive IL-10 deficiency are markers of intestinal inflammation (Vasovic et al., 2016). IL-6 is the main cytokine in the inflammatory region of ulcerative colitis patients, and its concentration is related to the score of disease severity under endoscopy (Zdravkovic et al., 2014).

The aggravation of colitis may result from S mutans infection of the liver, IFN-γ released from the liver during S mutans infection is the first step for various inflammatory cascade reactions (Kojima et al., 2012; Kojima et al., 2014).

Streptococcus mutans infection contributes to tumor invasiveness and is associated with poor disease control. In an oral squamous cell carcinoma mouse model, S. mutans promoted oral cancer development and progression by increasing IL-6 production (Tsai et al., 2022). S. mutans has the ability to induce vascular inflammation and disrupt the vascular barrier by upregulating IL-8, reducing vascular endothelial-cadherin expression, and enhancing intercellular adhesion molecule 1 signaling, thereby facilitating tumor cell extravasation and migration toward the endothelium (Yu et al., 2009; Yu et al., 2022; Figure 1).

The impairment of the vascular endothelium lead to cerebral hemorrhage, infective endocarditis and atherosclerosis. S. mutans can induce an upregulation of interleukin, which, in conjunction with its vascular damage, may contribute to the vascular metastasis of primary tumors.

During serotype k infection, the liver releases IFN-γ and triggers inflammation. This, combined with the interaction of type IV collagen, a basal membrane protein in parahepatic sinus cells, with S. mutans, can result in tissue fibrosis and non-alcoholic steatohepatitis. Simultaneously, IFN-γ released by the liver may be a primary factor in the exacerbation of colitis.

IgA immune reactions in Cnm + mucosal tissue may cause glycosylation defects in serum IgA1 molecules, with impaired glycosylation being the primary pathogenesis of IgAN. Immunofluorescence reveals IgA deposition in the mesangial region.