Oral streptococcae

Oral streptococci belong to the natural oral flora of humans. Of the twelve species of the genus Streptococcus, which are grouped together under the term oral streptococci, Streptococcus mutans, as the main causative agent of dental caries, is the only species that must be classified as pathogenic for humans.

In addition, oral streptococci are also found in the intestinal tract in the vagina. Their systematics and nomenclature are in flux. Most oral streptococci do not have antigen of the Lancefield grouping.

Many have alpha-hemolytic properties. For this reason, they are also called "greening streptococci" or "viridans streptococci". However, greening is not obligate. Some species show no haemolysis at all (gamma haemolysis).

Oral streptococci have the following pathological significance in medicine besides caries formation:

• They are the cause of bacterial endocarditis in >50%.
• They are the most common appendicitis pathogens (Hof H et al. 2019).

However, if oral streptococci get out of their natural habitat into other regions of the human body, they can develop considerable pathogenic potential there and cause severe infections. How oral streptococci evade the defense mechanisms of the human immune system, persist in the bloodstream, and colonize tissue structures of the human body is still only partially known. With an average of^{109 bacteria}per millilitre of saliva, the oral cavity is the most densely populated region of the body next to the colon.

Oral streptococci include:

"Salvarius group" (intestinal streptococci).

• S.salvcarius
• S.bovis

"Mutans group"

• S.mutans
• S.cricetus

"Milleri group"

• S.anginosus
• S.constellatus
• S.intermedius

"Oralis group"

• S.mitor
• S.mitis
• S.sanguis

In the oral cavity of an adult, 500 to 700 different bacterial species can be detected, of which some members of the genus Streptococcus are the most frequently isolated. These species, which belong to the group of oral streptococci, colonize all areas of the human oral cavity as commensals. The constant confrontation with the immune system of the host and continuous hygienic cleaning measures of the oral cavity are responsible for the fact that these bacteria do not multiply and spread unhindered. Nevertheless, it happens again and again that oral streptococci are also isolated from regions of the human body that do not correspond to their natural habitat and where they act as pathogens.

Agglutination of bacteria occurs by salivary proteins such as mucins, secretory IgA, salivary agglutinin, lysozyme and β2-microglobulin. In combination with salivary flow, agglutination makes it difficult for bacteria to attach to oral surfaces. The bacterial aggregates are swallowed and killed in the digestive tract by gastric acid. Saliva also contains a whole range of antibacterial proteins. Lysozyme, histatins and β-defensins have bactericidal effects. Lactoferrin and various salivary peroxidases have been shown to have a bacteriostatic effect.

Oral streptococci are unable to actively penetrate the pellicle and oral mucosa. However, injury to the mucosal surfaces causes the bacteria to enter the underlying tissues and bloodstream, often resulting in oral streptococcal bacteraemias. These occur not only during serious procedures such as tooth extractions (Bahrani-Mougeot FK et al. 2008) or tonsillectomies, but also during daily mechanical cleaning of tooth surfaces. In most cases, the immune system fights such bacteraemias so effectively that normally no foci of infection can manifest themselves (Tomás I et al. 2007). Nevertheless, cases are repeatedly reported in which oral streptococci cause serious illnesses such as

• Sepsis
• Streptococcus-induced toxic shock syndrome
• Endocarditis
• abscesses

(Ulivieri et al. 2007). The mechanisms leading to these syndromes have only been partially elucidated. The outbreak of streptococcal-induced "toxic shock syndrome " in Jiangsu Province in China was caused by Streptococcus mitis and has been attributed to a previously unknown exotoxin (Lu et al. 2003). How the gene of the toxin entered this oral streptococcal isolate remains unclear. However, genetic exchange between bacteria in the human oral cavity represents a possible cause.

Oral streptococci are also among the major causative agents of infective endocarditis. The species of the mitis group, Streptococcus sanguinis, Streptococcus oralis and Streptococcus gordonii are the most frequently isolated (Westling et al. 2008).

If oral streptococcal bacteremia reaches the heart via the bloodstream, there is a risk, especially in pre-damaged valvular tissue, that the bacteria will adhere there and colonize the tissue (Barrau et al. 2004). Two mechanisms for adhesion to damaged heart valve tissue discussed.

• If the tissue is damaged in such a way that components of the extracellular matrix become accessible, the bacteria can bind directly to this damaged site.
• Surface proteins that mediate binding to laminin and fibronectin (FbpA) have been described for Streptococcus gordonii (Christie et al. 2002).

Binding to immobilized fibronectin has been described for CshA, whereas the antigen I/II family adhesins SspA and SspB mediate binding to collagen. Similar adhesion mechanisms utilizing binding to extracellular matrix proteins have been described for other oral streptococcal species (Sato et al. 2004). If the damaged tissue is already protected by the formation of a thrombus, some oral streptococci are still able to adhere. A surface protein has been described for Streptococcus parasanguinis (FimA) that mediates binding to the major component of the thrombus, fibrin. Streptococcus gordonii can also bind directly to thrombus (Bensing et al. 2004).

The adhesin Hsa, which mediates binding to a salivary mucin in the oral cavity and thus initiates colonization of oral surfaces, has the function of a platelet adhesin in the bloodstream. In contrast, Streptococcus sanguinis is not only capable of adhering to a thrombus, but can also induce thrombus formation. A surface protein has been described (PAAP) that allows Streptococcus sanguinis not only to bind specifically to platelets, but also to activate them (Erickson et al. 1995).

The ability to bind platelets has only been described for Streptococcus sanguinis and Streptococcus gordonii. Furthermore, platelet activation has only been demonstrated in Streptococcus sanguinis isolates (Douglas et al. 1990). The pathogenesis of other important endocarditis pathogens such as Streptococcus mitis or Streptococcus oralis remains unclear.

Virulence factors in streptococci

• Adhesins: For obligate pathogenic streptococcal species such as Streptococcus pyogenes, Streptococcus agalactiae or Streptococcus pneumoniae, a whole series of adhesins, antiphagocytic surface proteins and exotoxins have been described to which the pathogenicity of these bacteria is attributed ( Jedrzejas MJ (2004). Surface proteins that mediate binding to components of the extracellular matrix such as fibronectin (SfbI, SfbII, Fnz, Fnb, GfbA), collagen (Cpa) or laminin (Lmb) allow attachment to human tissue structures and thus initiate colonization (Nitsche-Schmitz et al.2007).
• Accumulation of fibrinogen/immunoglobulins: To escape phagocytosis, many obligate pathogenic streptococci accumulate fibrinogen by binding to the M protein on the bacterial surface. Numerous pathogenic streptococci of the pyogenic group are also capable of actively counteracting opsonization by immunoglobulins. Surface proteins have been described that bind human immunoglobulins thus on the bacterial surface. In addition, extracellular bacterial proteases have been described (ScpA, ScpB, CppA) that proteolytically inactivate key factors of the complement system (Angel et al. 1994).
• Hemolysins: Hemolysins represent another antiphagocytic mechanism described in pathogenic streptococci of the pyogenic group. Hemolysins from Streptococcus pyogenes (SLO, SLS) are not only capable of lysing erythrocytes and causing the β-hemolysis typical of these bacteria, but also have a cytotoxic effect on cells of the immune system (Timmer et al. 2009).
• Pyogenic exotoxins and superantigens: Some pathogenic streptococci of the pyogenic group prevent the immune system from effectively fighting bacterial infections by inducing an exuberant immune response (streptococcal-induced toxic shock syndrome). For this purpose, the bacteria secrete so-called pyogenic exotoxins and superantigens (SpeA, SpeC, SpeJ).
• Spreading factors: In order to facilitate rapid spread in tissues, many obligate pathogenic streptococci secrete tissue-degrading enzymes, which are grouped under the term spreading factors. These include proteins (streptokinases) that convert plasminogen into its active form and thus activate host proteolysis systems in a cascade-like manner (Lähteenmäki et al. 2001). Also to be counted among the spreading factors are hyaluronidases, which degrade the structure-giving hyaluronic acid network of the extracellular matrix (Starr et al., 2006), and secreted proteases, which not only degrade structural proteins but can also inactivate signal molecules of the immune system.

1. Angel CS et al (1994) Degradation of C3 by Streptococcus pneumoniae. J Infect Dis. 170:600-608.
2. Bahrani-Mougeot FK et al. (2008) Diverse and novel oral bacterial species in blood following dental procedures. J Clin Microbiol 46:2129-2132.
3. Barrau K et al (2004) Causative organisms of infective endocarditis according to host status. Clin Microbiol Infect 10:302-308.
4. Bensing BA et al.(2004) The Streptococcus gordonii surface proteins GspB and Hsa mediate binding to sialylated carbohydrate epitopes on the platelet membrane glycoprotein Ibalpha. Infect Immun. 72:6528-6537.
5. Christie J et al (2002) Expression of fibronectin-binding protein FbpA modulates adhesion in Streptococcus gordonii. Microbiology 148:1615-1625.
6. Douglas CW et al (1993) Identity of viridans streptococci isolated from cases of infective endocarditis. J Med Microbiol 39:179-182.
7. Erickson PR et al.(1995) Altered expression of the platelet aggregationassociated protein from Streptococcus sanguis after growth in the presence of collagen. Infect Immun 63:1084-1088.
8. Hof H et al (2019) Oral streptococci. In: Hof H, Schlüter D, Dörries R, eds Duale Reihe Medizinische Mikrobiologie. 7th, completely revised and expanded edition. Stuttgart: Thieme S 346
9. Jedrzejas MJ (2004) Extracellular virulence factors of Streptococcus pneumoniae. Front Biosci 9:891-914. review.
10. Lähteenmäki K et al (2001) Bacterial plasminogen activators and receptors. FEMS Microbiol Rev 25:531-552.
11. Lu HZ et al (2003) Major outbreak of toxic shock-like syndrome caused by Streptococcus mitis. J Clin Microbiol 41:3051-3055.
12. Nitsche-Schmitz DP et al. (2007) Group G streptococcal IgG binding molecules FOG and protein G have different impacts on opsonization by C1q. J Biol Chem 282:17530-17536.
13. Sato Y et al (2004) Streptococcus mutans strains harboring collagen-binding adhesin. J Dent Res 83:534-539.
14. Timmer AM et al (2009) Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J Biol Chem 284:862-871.
15. Tomás I et al. (2007) Prevalence, duration and aetiology of bacteraemia following dental extractions. Oral Dis 13:56- 62.
16. Ulivieri S et al. (2007) Brain abscess following dental procedures. Case report. Minerva Stomatol. 56:303-305.
17. Westling K et al.(208) Identification of species of viridans group streptococci in clinical blood culture isolates by sequence analysis of the RNase P RNA gene, rnpB.J Infect 56:204-210.