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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

Streptococcus 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 Streptococcus intermedius BA1, Streptococcus intermedius C270, and Streptococcus 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 Streptococcus intermedius strains have 37 – 38% GC content [1][16][22]. Streptococcus 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

Streptococcus 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]. Streptococcus 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 Streptococcus anginosus group via Lancefield group antigens and hemolysis, it has been frequently confirmed that Streptococcus 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]. Streptococcus 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 Streptococcus intermedius to grow on macromolecules found in host tissue [23-25][28 - 31]. These hydrolytic enzymes allow Streptococcus 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].

References

[1] [http://www.researchgate.net/publication/21161040_Emended_descriptions_and_recognition_of_Streptococcus_constellatus_Streptococcus_intermedius_and_Streptococcus_anginosus_as_distinct_species Whiley, R.A., and Beighton, D. 1991. Emended descriptions and recognition of ‘’Streptococcus constellatus’’, ‘’Streptococcus intermedius’’, and ‘’Streptococcus anginosus’’ as distinct species. International Journal of Systematic Bacteriology 41(1): 1-5.]

[2] Whiley R.A., Fraser, H., and Beighton, D. 1990. Phenotypic differentiation of ‘’Streptococcus intermedius’’, ‘’Streptococcus constellatus’’, and ‘’Streptococcus anginosus’’ strains within the “’’Streptococcus milleri’’ Group”. Journal of Clinical Microbiology 28(7): 1497 – 1501.

[3] Facklam, R. 2002. What happened to the Streptococci: overview of taxonomic and nomenclature changes. Clinical Microbiology Reviews 15(4): 613 – 630.

[4] Bentley, R.W., Leigh, J.A., and Collins, M.D. 1991. Intrageneric structure of Streptococcus based on comparative analysis of small-subunit rRNA sequences. International Journal of Systematic Bacteriology 41(4): 487 – 494.

[5] Whiley, R.A., and Hardie, J.M. 1989. DNA-DNA hybridization studies and phenotypic characteristics of strains within the “’’Streptococcus milleri’’ Group” 135: 2623 – 2633.

[6] Ruoff, K.L. 1988. ‘’Streptococcus anginosus’’ (“’’Streptococcus milleri’’”): the unrecognized pathogen. Clinical Microbiological Reviews 1(1)” 102 – 108.

[7] Coykendall, A.L., Wesbecher, P.M., and Gustafson, K.B. 1987. “’’Streptococcus milleri’’,” ‘’Streptococcus constellatus’’, and ‘’Streptococcus intermedius’’ are later synonyms of ‘’Streptococcus anginosus’’. International Journal of Systematic Bacteriology 37: 222-228.

[8] Ball, L.C., and Parker, M.T. 1979. The cultural and biochemical characters of ‘’Streptococcus milleri’’ strains isolated from human sources. The Journal of Hygiene 82(1): 63 – 78.

[9] Facklam. R.R. 1977. Physiological differentiation of viridans streptococci. Journal of Clinical Microbiology 5(2): 184 -201.

[10] [http://link.springer.com/article/10.1007%2FBF02148689 Labbé, M., Van der Auwera, P., Glupczynski, Y., Crockaert, F., and Yourassowsky, E. 1985. Fatty acid composition of ‘’Streptococcus milleri’’. European Journal of Clinical Microbiology and Infectious Diseases 4(4): 391 – 393.

[11] Jacobs, J.A., Schot, C.S., and Schouls, L.M. 2000. The ‘’Streptococcus anginosus’’ species comprises five 16S rRNA ribogroups with different phenotypic characteristics and clinical relevance. International Journal of Systematic and Evolutionary Microbiology 50: 1073 – 1079.

[12] Whiley, R.A., Beighton, D., Winstanley, T.G., Fraser, H.Y., and Hardie, J.M. 1992. ‘’Streptococcus intermedius’’, ‘’Streptococcus constellatus’’, and ‘’Streptococcus anginosus’’ (the ‘’Streptococcus milleri’’ group): association with different body sites and clinical infections. Journal of Clinicla Microbiology 30: 243 – 244.

[13] The National Center for Biotechnology Information.

[14] Whiley, R.A., Freemantle, L., Beighton, D., Radford, J.R., Hardie, J.M., and Tillotsen, G. 1993. Isolation, identification and prevalence of ‘’Streptococcus anginosus’’, ‘’S. intermedius’’ and ‘’S. constellatus’’ from the human mouth. Microbial Ecology in Health and Disease 6: 285 – 291.

[15] Rabe, L.K., Winterscheid, K.K., and Hillier, S.L. 1988. Association of viridans group streptococci from pregnant women with bacterial vaginosis and upper genital tract infection. Journal of Clinical Microbiology 26(6): 1156 – 1160.

[16] Planet, P.J., Rampersaud, R., Hymes, S.R., Whittier, S., Della-Latta, P.A., Narechania, A., Daugherty, S.C., Santana-Cruz, I., DeSalle, R., Ravel, J., and Ratner, A.J. 2013. Genome sequence of the human abscess isolate ‘’Streptococcus intermedius’’ BA1. Genome Announcements 1(1): 1 – 2.

[17] Clarridge, J.E., Attorri, S., Musher, D.M., Hebert, J., and Dunbar, S. 2001. ‘’Streptococcus intermedius’’, ‘’Streptococcus constellatus’’, and ‘’Streptococcus anginosus’’ (“’’Streptococcus milleri’’ Group”) are of different clinical importance and are not equally associated with abscess. Clinical Infectious Diseases 32(10): 1511 – 1515.

[18] Bantar, C., Canigia, L.F., Relloso, S., Lanza, A., Bianchini, H., and Smayevsky, J. 1996. Species belonging to the “’’Streptococcus milleri’’” group: antimicrobial susceptibility and comparative prevalence in significant clinical specimens. Journal of Clinical Microbiology 34(8): 2020 – 2022.

[19] Flynn, C.E., and Ruoff, K.L. 1995. Identification of “’’Streptococcus milleri’’” group isolates to the species level with a commercially available rapid test system. Journal of Clinical Microbiology 33(10): 2704 – 2706.

[20] Parker, M.T., and Ball, L.C. 1976. Streptococci and aerococci associated with systemic infection in man. Journal of Medical Microbiology 9(3): 275 – 302.

[21] Nagamune, H., Ohnishi, C., Katsuura, A., Fushitani, K., Whiley, R.A., Tsuji, A., Matsuda, Y. 1996. Intermedilysin, a novel cytotoxin specific for human cells secreted by ‘’Streptococcus intermedius’’ UNS46 isolated from a human liver abscess. Infection and Immunity 64(8): 3093 – 3100.

[22] Olson, A.B., Kent, H., Sibley, C.D., Grinwis, M.E., Mabon, P., Ouellette, C., Tyson, S., Graham, M., Tyler, S.D., Domselaar, G.V., Surette, M.G., and Corbett, C.R. 2013. Phylogenetic relationship and virulence inference of ‘’Streptococcus anginosus’’ group: curated annotation and whole-genome comparative analysis support distinct species designation. BMC Genomics 14: 895.

[23] Shain, H., Homer, K.A., and Beighton, D. 1996. Degradation and utilisation of chondroitin sulphate by ‘’Streptococcus intermedius’’. Journal of Medical Microbiology 44: 372 – 380.

[24] Homer, K., Shain, H., and Beigton, D. 1997. The role of hyaluronidase in growth of ‘’Streptococcus intermedius’’ on hyaluronate. Advances in Experimental Medicine and Biology 418: 681 – 683.

[25] [http://www.researchgate.net/publication/233788624_The_role_of_Streptococcus_intermedius_in_brain_abscess Mishra, A.K., and Fournier, P.E. 2012. The role of ‘’Streptococcus intermedius’’ in brain abscess. European Journal of Clinical Microbiology and Infectious Diseases; online.]

[26] Tran, M.P., Caldwell-McMillan, M., Khalife, W., and Young, V.B. 2008. ‘’Streptococcus intermedius’’ causing infective endocarditis and abscesses: a report of three cases and review of the literature. BMC Infectious Disease 8: 154.

[27] Wells, C.L., Wilkins, T.D. Anaerobic Cocci. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 19.

[28] Beighton, D., and Whiley, R.A. 1990. Sialidase activity of the “’’Streptococcus milleri’’ group” and other viridans group streptococci. Journal of Clincial Microbiology 28(6): 1431 – 1433.

[29] Nagamune, H., Whiley, R. A., Goto, T., Inai, Y., Maeda, T., Hardie, J. M., and Kourai, H. 2000. Distribution of the intermedilysin gene among the anginosus group streptococci and correlation between intermedilysin production and deep-seated infection with ‘’Streptococcus intermedius’’. Journal of Clinical Microbiology 38(1): 200 – 226.

[30] Homer, K.A., Denbow, L., Whiley, R.A., and Beighton, D. 1993. Chondroitin sulfate depolymerase and hyalornidase activities of viridans streptococci determined by a sensitive spectrophotometric assay. Journal of Clinical Microbiology 31(6): 1648 – 1651.

[31] Homer, K.A., Whiley, R.A., and Beighton, D. 1994. Production of specific glycosidase activities by ‘’Streptococcus intermedius’’ strain UNS35 grown in the presence of mucin. Journal of Medical Microbiology 41: 184 – 190.

[32] Pecharki, D., Petersen, F. C., and Scheie A. Aa. 2008. Role of hyaluronidase in ‘’Streptococcus intermedius’’ biofilm. Microbiology 154: 932-938.

[33] Ahmed, N.A., Petersen, F.C., and Scheie, A.A. 2009. AI 2/LuxS is involved in increased biofilm formation by ‘’Streptococcus intermedius’’ in the presence of antibiotics. Antimicrobial Agents and Chemotherapy 53(10): 4258 – 4263.

[34] Ahmed, N.A.A.M., Petersen, F.C., and Scheie, A.A. 2008. Biofilm formation and autoinducer-2 signaling in ‘’Streptococcus intermedius’’: role of thermal and pH factors. Oral Microbiology and Immunology 23(6): 492 – 497.

[35] Shinzato, T., and Saito, A. 1995. The ‘’Streptococcus milleri’’ group as a cause of pulmonary infections. Clinical Infectious Diseases 21(3): 238 – 243.

[36] Okayama, H., Nagata, E., Ito, H.O., Oho, T., and Inoue, M. 2005. Experimental abscess formation caused by human dental plaque. Microbiology and Immunology 49(5): 399 – 405.

[37] Macey, M.G., Whiley, R. A., Miller, L., and Nagamun, H. 2001. Effect on polymorphonuclear cell function of a human-specific cytotoxin, intermedilysin, expressed by ‘’Streptococcus intermedius’’. Infection and Immunity 69(10): 6102-6109.