Streptococcus salivarius

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1. Classification

a. Higher order taxa

Domain: Bacteria
Phylum: Firmicutes
Class: Bacilli
Order: Lactobacillales
Family: Streptococcaceae
Genus: Streptococcus
Species: Streptococcus salivarius

2. Description and significance

S. salivarius is a spherical, Gram-positive, facultative anaerobic commensal bacterium that is both catalase and oxidase negative. As one of the first colonizers of the human oral cavity, upper respiratory tract, and gut after birth, S. salivarius is thought to contribute to immune homeostasis and regulate inflammatory response. Thus, the bacterium is most often harmless but considered an opportunistic pathogen (1).

Humans are introduced to S. salivarius within a few hours after birth, inhabiting the mouth and upper respiratory tract, making it one of the first commensal bacteria humans are exposed to (2). Early exposure allows humans to acquire immunity, so S. salivarius is usually considered harmless. However, while immunity is established during infancy, the bacteria are opportunistic pathogens, proving to be detrimental under certain circumstances, such as entrance to the bloodstream (3). Due to its opportunistic nature, S. salivarius has been linked to cases of sepsis in immunocompromised patients with neutropenia, a disease associated with a depleted level of white blood cells in the body (3).

3. Genome structure

The entire genome structure of a clinical strain CCHSS3 of S. salivarius was sequenced using the Sanger shotgun method to produce a draft of the genome, and Next Generation Sequencing was used to revise and correct any sequencing errors (4). The initial draft was assembled into 374 contigs, which were then ordered and gaps were closed. Finally, IS boundaries were sequenced, and mismatch and small corrections were carried out by SOLiD sequencing technology with 110-fold coverage to ensure correct assembly and sequence accuracy (4). The circular chromosome of S. salivarius CCHSS3 consists of 2.2 million base pairs with a GC-content of 40% (4). It comprises of 2032 genes, with 2027 that encode for proteins; there are also 68 tRNA genes that encompass all the amino acids, and 6 rRNA operons (4).
There is a complete genome sequence available for the S. salivarius strain JIM8777. The genome of the strain JIM8777 consists of genes that help regulate the oral community. These genes include those involved in lactose uptake, urea catabolism, and bacteriocin production. (5)
The sequencing of the S. salivarius genome revealed a gene similar to the stress resistance gene ClpP in Escherichia coli. Stress resistance genes encode for stress-induced proteins such as chaperones that help refold denatured proteins or proteases that degrade them; these proteins allow the bacteria to survive under stress. ClpP is also found in several other bacteria, including Yersinia enterocolitica and Pseudomonas fluorescens, and was shown to have slightly different functions, such as conferring virulence and participating in biofilm formation (1). ClpP is found to be under the regulation of two repressor proteins, CtsR and HrcA. A study led by Chastanet and Msadek showed that repression is lifted during growth in high temperatures, allowing the production of heat-shock proteins from the clpP gene (1). It is unknown whether the similar gene found in S. salivarius have the same heat-resistant properties. Therefore, additional research would be helpful in determining whether S. salivarius is able to thrive at relatively high temperatures, which makes the bacteria more difficult to exterminate with high heat alone.

4. Cell structure

S. salivarius is a Gram-positive cocci so Gram stain results would show a purple stain under the microscope due to crystal-violet dye’s affinity to the thick peptidoglycan layer. S. salivarius contains a peptidoglycan layer specifically called murein, which provides protection and rigidity, and helps shape the cell. Murein is a characteristic polymer of bacteria making it a good target for antibiotics.

5. Metabolic processes

S. salivarius is a facultative anaerobe (6). Facultative anaerobes perform respiration in the presence of oxygen. In situations where oxygen is not readily available, facultative anaerobes can switch to fermentation or anaerobic respiration to generate ATP. Since food from the host enters the oral cavity, the amount of nutrients that S. salivarius, as well as other bacteria residing in the oral cavity, are essentially non-limiting. S. salivarius strain JIM8777 was found to contain a gene conferring lactose catabolism (5), which allows the bacteria to thrive in areas such as the oral cavity where such sugars can be found.

6. Ecology

S. salivarius is found in the upper respiratory tract and oral cavity of the human body. While the bacterium is part of the normal flora in those environments, its entrance to the bloodstream causes it to become pathogenic (3).
Several strains of S. salivarius are able to interfere with respiratory pathogens and metabolites present in S. salivarius can trigger inhibition of NF-κB activation in human IECs (2). Specific strains of S. salivarius, such as S. salivarius TOVE-R and K12, have been reported to be successful antagonists of virulent streptococci, which has been attributed to its bacteriocin production (2). S. salivarius K12’s production of bacteriocins show inhibitory activity against halitosis-associated species (7). Different strains of S. salivarius are capable of producing bacteriocins called lantibiotics. Lantibiotics have the potential to treat infectious diseases and thus further research on how S. salivarius can act as a probiotic can lead to new discoveries of treatments in medicine. (8)

7. Pathology

S. salivarius has been linked to cases of sepsis in people with neutropenia, a disease associated with a depleted level of white blood cells in the body (3). Sepsis occurs when the immune system becomes compromised, which allows the bacteria to attack when immune cells are weakened. They can also cause disease if they enter the bloodstream via dental work (3).

8. Current Research

Potential as a Probiotic
Recent research has been done on S. salivarius investigating the efficacy of the use of certain strains of the bacteria as probiotics. Probiotics are defined as live organisms that are ingested in defined amounts to confer a health benefit to the host. Bacteria from the gastrointestinal tract have been the conventional source for probiotics. Administering probiotics using bacteria from the ear and oral cavity is therefore a relatively new concept, but has shown to have promise in enhancing overall health. This linkage is due to the fact that many human diseases are associated either directly (e.g. dental caries) or indirectly (e.g. cardiovascular diseases) to oral microbiota disequilibria (9).
The probiotic S. salivarius M18 was studied by Burton JP et al, and was shown to have potential as a probiotic in the oral microbiome (9). The study was performed on a randomized group of 100 children with active tooth decay conditions. After three months of M18 treatment administration, the participants were examined for their changes in plaque and overall tissue health. Plaque scores were significantly lower following the M18 treatment. The trial also revealed that this strain produces bacteriocins that target Streptococcus mutans, a tooth decay-causing bacteria found in the oral cavity. The production of enzymes that reduce dental plaque accumulation and acidification also proved the M18 strain to be a helpful probiotic (9).

Ear Cavity Health Benefits
S. salivarius K12 also has a beneficial effect on ear health in humans. A bacteriotherapy trial has been conducted which tested the potential benefits of S. salivarius by administering a nasal spray containing a strain of S. salivarius to children with recurrent acute otitis media, or middle ear infection (10). The invasion of bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes into the middle ear can cause acute otitis media (AOM), or middle ear infection, and on occasion secretory otitis media (SOM). More than 80% of preschool children have at least one episode of AOM or SOM (10). Spray treatment of S. salivarius K12 showed that AOM incidence dropped by about 40% per month, and pure tone audiometry improved for both ears (10). In addition, no side effects were seen in any of the children in the clinical study (10). Although this study is only a starting point in this area of research, it provides a basis for investigating the treatment of ear infections and maintaining ear cavity health.

Use for Reduction of Halitosis
Probiotic S. salivarius K12 was also tested on its ability to reduce the severity of halitosis (i.e. bad breath) (7). Twenty three subjects were given either a tablet containing the K12 strain or a placebo. Following the three-day regimen, the severity of halitosis was assessed by analyzing their volatile sulfur compound levels. The bacterial composition of their saliva was also analyzed in culture (7). Results indicated that the severity of halitosis did decrease, and S. salivarius K12 inhibited the growth of a black-pigmented bacteria as well as other bacteria linked to halitosis (7). Therefore, S. salivarius K12 competitively colonized the areas that other bacteria had colonized and could be an effective solution to reducing the severity of halitosis (7).

Anti-Inflammatory Properties
Another characteristic of S. salivarius includes its ability to inhabit the oral cavity soon after birth, providing an anti-inflammatory mechanism for the infant. S. salivarius can be used to treat atypical pneumonia. S. salivarius is a probiotic bacterium that can inhibit pneumococcal adherence to pharyngeal epithelial cells (11). A particular study closely examined the effects of two different strains of S. salivarius (K12 and M18) on a human pharyngeal epithelial cell line (Detroit 562/D562) to investigate the methods of inhibition (11). Results revealed that the bacterium utilizes a mechanism that blocks pneumococcal binding sites, which in turn reduces the pneumococcal adherence to pharyngeal epithelial cells (11). However, inhibition occurs depending on the strain of S. salivarius and its dosage (11). Therefore, further research is required to determine if the blockage of the pneumococcal binding site is coincidental to the presence of S. salivarius. Understanding how probiotics such as S. salivarius may work to inhibit pneumococcal adherence is key to the potential development of new strategies to prevent pneumococcus colonization (11).

9. References

(1) Chastanet, A and Msadek, T. (2003) clpP of Streptococcus salivarius Is a Novel Member of the Dually Regulated Class of Stress Response Genes in Gram-Positive Bacteria. Journal of Bacteriology, 185(2): 683-687.
(2) Kaci G, Goudercourt D, Dennin V, Pot B, Dore J, Ehrlich SD, et al. (2014) Anti-inflammatory properties of Streptococcus salivarius, a commensal bacterium of the oral cavity and digestive tract. Appl Environ Microbiol 80(3): 928–34.10.1128/AEM.03133-13.
(3) Tunkel, A. R. and Sepkowitz, K. A. (2002). Infections Caused by Viridans Streptococci in Patients with Neutropenia. Clinical Infectious Diseases 34:1524-9.
(4) Delorme C, Guédon E, Pons N, Cruaud C, et al. (2011) Complete Genome Sequence of the Clinical Streptococcus salivarius Strain CCHSS3. Journal of Bacteriology, 193(18), 5041–5042.
(5) Guedon E, Delorme C, Pons N et al. (2011) Complete genome sequence of the commensal Streptococcus salivarius strain JIM8777. Journal of Bacteriology, 193(18): 5024–5025.
(6) Salako NO, Rotimi VO, Preeta R, Khodakhast F. (2004) The Bacteriology of the Supragingival Plaque of Child Dental Patients in Kuwait. Medical Principles and Practice 13:191-195.
(7) Burton JP, Chilcott CN, Moore CJ, Speiser G and Tagg JR. (2006) A preliminary study of the effect of probiotic Streptococcus salivarius K12 on oral malodour parameters. Journal of Applied Microbiology, 100: 754–764.
(8) Barbour, A and Philip, K. (2014) Variable characteristics of bacteriocin-producing Streptococcus salivarius strains isolated from Malaysian subjects. PLoS One 9(6).
(9) Burton JP, Drummond BK, Chilcott CN et al. (2013) Influence of the probiotic Streptococcus salivarius strain M18 on indices of dental health in children: a randomized double-blind, placebo controlled trial. Journal of Medical Microbiology, 62: 875-884.
(10) Pierro F, Pasquale D, and Cicco M. (2015) Oral Use of Streptococcus Salivarius K12 in Children with Secretory Otitis Media: Preliminary Results of a Pilot, Uncontrolled Study. International Journal of General Medicine, 8: 303–308.
(11) Manning J, Dunne EM, Wescombe PA et al. (2016) Investigation of Streptococcus salivarius-mediated inhibition of pneumococcal adherence to pharyngeal epithelial cells. BMC Microbiology, 16: 225.