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Classification

Higher order taxa

Bacteria; Firmicutes; Bacilli; Lactobacillales; Streptococcaceae; Streptococcus

Species

NCBI: [1]

Streptococcus Intermedius

History

Before Streptococcus intermedius was recognized as a distinct species, it was classified as Streptococcus anginosus. This was the taxonomically accepted name for a single species that included S. intermedius, Streptococcus constellatus, and S. anginosus. Before these three strains were collectively known as S. anginosus, they were formerly and collectively known as the single species Streptococcus milleri, which was the taxonomically unaccepted bacterial name. Now each of these strains has been recognized and classified as distinct species and is a member of the Anginosus group streptococci [1-5][41].

The taxonomy and nomenclature of the species that are members of the S. anginosus group is a work in progress [3][6]. Both the terms S. milleri and S. anginosus were originally used to define the three streptococci as one species even though they have diverse serologic and biochemical characteristics [1][3][6][7]. The basis for the unification of these streptococci was the yield of similar results for a number of phenotypic tests, such as hemolytic and Lancefield grouping reactions, lactose fermentation, and fatty acid composition, and conflicting results from different studies; some DNA-DNA hybridization studies have concluded these strains form a single DNA homology group while others have identified several groups [1][2][7-10][17]. However, recent studies utilizing DNA-DNA reassociation, 16S rRNA analysis, and an identification scheme based on the degradation of chromogenic substrates have not only clarified the taxonomy and nomenclature of the group of species comprising the S. anginosus group, but also confirmed that the organisms that are members of this group are indeed distinct species [1][2][4][5][11]. Despite initial reservations about whether there were specific phenotypic traits that could differentiate the three species, Whiley et al. observed results, when proposing an identification scheme, that demonstrated each strain having certain hemolytic and Lancefield grouping reactions; the majority of strains of S. intermedius are nonhemolytic and serologically ungroupable whereas the majority of strains of S. anginosus and S. constellatus belong to Lancefield serological group F and are nonhemolytic and beta-hemolytic respectively [1-3]. However based on results from that study, Whiley et al. observed that hemolytic and Lancefield grouping reactions are not of primary importance in distinguishing these three strains but the ability to produce high levels of certain substrates is; S. intermedius produced a variety of substrates such as α-glucosidase and β-galactosidase, whereas S. constellatus produced β-glucosidase. It was also observed that the combination of these tests and other biochemical tests, such as fermentation of amygdalin, mannitol, and raffinose, and the production of hydrogen peroxide, could help give additional information of these strains in clinical studies [1][2]. This same study and Clarridge et al. have shown that each of these strains are associated with different clinical sources and this relationship can help differentiate these three species. S. intermedius is associated with abscesses of the brain and liver while S. anginosus and S. constellatus are commonly isolated from a wider range of sites [12][17].

Description and significance

S. intermedius is a Gram-positive bacterium that is a part of the normal flora in the oral cavity, as well as the upper respiratory, female urogenital, and gastrointestinal tracts [1][14-16][18][21]. It may also be found in human feces and is the dominant species found in subginival plaque [14][27]. Although this organism is a commensal organism of the habitats listed above, it is also an opportunistic pathogen [27]. Findings from a recent study suggest that this species is the most pathogenic of the species that comprise the S. anginosus group because it can cause abscesses by itself and is frequently found in blood culture whereas S. constellatus and S. anginosus are more likely to cause an abscess with the presence of other bacterial species. S. constellatus is also infrequently found in blood culture [17]. S. intermedius is usually found as a solitary isolate associated with deep – seated purulent abscesses, typically found in the brain or liver, central nervous system infections, and infective endocarditis [1-3][12][17][19][20][25][26].

Genome structure

The genomes of S. intermedius BA1, S. intermedius C270, and S. intermedius B196 are singular circular chromosomes that are 1.96, 1.96, and 1.99 Mbp long respectively [16][22]. The DNA base composition for these three fully sequenced S. intermedius strains have 37 – 38% GC content [1][16][22]. S. intermedius BA1, C270, and B196 have: 63, 60, and 60 tRNA genes respectively, 6, 4, and 4 rRNA genes respectively, and 2028, 1778, and 1815 coding DNA sequences with average gene lengths of 848, 949, and 952 nucleotides that comprised 87%, 86.09%, and 86.53% of the genome respectively [16][22]. Virulence genes, which are important to the pathogenesis of this organism, were also identified in these genome sequences, such as intermedilysin, a human erythrocyte specific cytotoxin, capsular polysaccharide synthesis, important for immune evasion, hyaluronidase, LPxTG motif proteins, adhesins, sialidases, and virulence factors similar to that of S. pneumoniae such as two-component histidine kinase systems [16][22].

Cell Structure and Metabolic Processes

S. intermedius is small, Gram-positive, non-sporeforming, nonmotile, cocci, and an aerotolerant anaerobe [1][27]. It is saccharolytic, meaning that it breaks down sugars in metabolism for energy production [27]. S. intermedius produces acid from the following sugars: glucose, trehalose, lactose, amygdalin, cellobiose, salicin, mannitol, melibiose, and raffinose [1][2][27]. Catalase is not found in this bacterium and it does not produce hydrogen peroxide [1]. Although it is difficult to distinguish the three species of the S. anginosus group via Lancefield group antigens and hemolysis, it has been frequently confirmed that S. intermedius is associated with no Lancefield group antigens and are nonhemolytic [1-3][9]. Another characteristic of this organism is that it forms biofilms to protect itself from antibiotics and the host immune system [25]. This is a process where the cells become attached to the host surface in dense aggregates, produce extracellular polymers, mature, and then disperse [25][32]. S. intermedius uses quorum sensing to communicate within its’ population [33]. More specifically, it uses the autoinducer signaling system AI 2/LuxS to accomplish this communication and the formation of biofilms [33][34]. Also a recent study on the effects of temperature and pH on biofilm formation has shown that high temperature and acidic conditions may favor increased biofilm formation [34].

This organism also produces hydrolytic enzymes, including both glycosoaminoglycan degrading enzymes, such as hyaluronidase and chrondroitin sulphate depolymerase, and glycosidases, such as α- N- acetylneuramidase (sialidase), β-D-galactosidase, N-acetyl-β-D-glucosaminidase, and N-acetyl-β-D-galactosaminidase, which allow S. intermedius to grow on macromolecules found in host tissue [23-25][28 - 31]. These hydrolytic enzymes allow S. intermedius to produce small nutrient molecules to be used for metabolic processes [1][25][29-31].

Ecology

A recent study has shown that the S. anginosus group is in a synergistic relationship with oral anaerobes found in pulmonary infections [35]. Another study observed the prevalence and distribution of the three species in different sites of the oral cavity; samples were taken from supragingival plaque and saliva, subgingival samples, and mouth rinses. For a majority of the sites, S. intermedius and S. anginosus were observed singly or together whereas the harboring of S. intermedius and S. constellatus or of all three species was observed rarely [14]. S. intermedius could have an effect on the ability of S. anginosus to form abscesses [36].

Pathology

The association of S. intermedius with deep-seated purulent abscesses has been recognized for a long time; the first case was reported in 1975 [25]. However, the determination of what contributes to its’ pathogenicity and the mechanisms behind it is an ongoing area of research. A recent study has shown that hyaluronidase, an enzyme that breaks down host tissues and allows the bacteria to then utilize the products for growth, may play a role in the dispersal of the biofilm of S. intermedius [32]. There have also been many studies on the cytotoxin intermedilysin as it plays a role in the pathogenicity of S. intermedius [21][29][37][38]. Cytotoxin intermedilysin specifically targets and lyses human cells, decreases the number of neutrophils or fully functioning polymorphonuclear cells, and is produced 6.2 to 10.2 times more in deep-seated infections than the normal habitats of S. intermedius [21][29][37][38]. Intermedilysin may be the triggering factor for the formation of deep-seated purulent infections since no correlation was seen between enzymatic activity and isolation sites of other known virulence factors [29]. Another study has shown that the surface protein Antigen I/II of S. intermedius is involved with adhesion to fibronectin and laminin, which is an important step in the pathogenesis of endocarditis and formation of abscesses [39].

Current Research

Ongoing research is focused on elucidating the mechanisms behind the pathogenicity of the different virulence factors of S. intermedius [21][29][37][38]. There is also a research effort to develop rapid biomolecular methods to identify S. intermedius accurately against the other species in the S. anginosus group [19], and to determine its antibiotic resistance. One study demonstrates that S. anginosus and S. intermedius are starting to display resistance to penicillin [18]. Also, there are three commercial identification systems available that utilize three of the seven chromogenic substrates suggested by Whiley et al., the Fluo-Card Milleri system, the Rapid ID-32 Strep system, and the Becton Dickinson Microbiology Crystal Gram-Positive system [3]. Treatment options for S. intermedius are in development [18][40]. One study examined and compared two methods, lethal photosensitization and sodium hypochlorite irrigation, in efficacy of killing S. intermedius biofilms. The results demonstrated that while lethal photosensitization did kill S. intermedius biofilms, it did not achieve total kill like sodium hypochlorite irrigation, which is the method traditionally used in contemporary treatment procedures to eliminate infection in root canals [40].