The species name is derived from Greek words meaning 'a chain' (streptos) of berries (coccus [Latinized from kokkos]) and pus (pyo)-forming (genes), since a number of infections caused by the bacterium produce pus. The main criterion for differentiation between Staphylococcus spp. and Streptococcus spp. is the catalase test. Staphylococci are catalase positive whereas streptococci are catalase-negative.[2]S. pyogenes can be cultured on fresh blood agar plates. The PYR test allows for the differentiation of Streptococcus pyogenes from other morphologically similar beta-hemolytic streptococci (including S. dysgalactiae subsp. esquismilis) as S. pyogenes will produce a positive test result.[3]
An estimated 700 million GAS infections occur worldwide each year. While the overall mortality rate for these infections is less than 0.1%, over 650,000 of the cases are severe and invasive, and these cases have a mortality rate of 25%.[4] Early recognition and treatment are critical; diagnostic failure can result in sepsis and death.[5][6]S. pyogenes is clinically and historically significant as the cause of scarlet fever, which results from exposure to the species' exotoxin.[7]
Epidemiology
Chains of S. pyogenes bacteria (orange) at 900× magnificationGram stain of Streptococcus pyogenes.
Unlike most bacterial pathogens, S. pyogenes only infects humans. Thus, zoonotic transmission from an animal (or animal products) to a human is rare.[8]
S. pyogenes typically colonizes the throat, genital mucosa, rectum, and skin. Of healthy adults, 1% to 5% have throat, vaginal, or rectal carriage, with children being more common carriers. Most frequently, transmission from one person to another occurs due to inhalation of respiratory droplets, produced by sneezing and coughing from an infected person. Skin contact, contact with objects harboring the bacterium, and consumption of contaminated food are possible but uncommon modes of transmission. Streptococcal pharyngitis occurs most frequently in late winter to early spring in most countries as indoor spaces are used more often and thus more crowded. Disease cases are the lowest during autumn.[9]
Maternal S. pyogenes infection usually happens in late pregnancy, at more than 30 weeks of gestation to four weeks postpartum. Maternal infections account for 2 to 4% of all clinically diagnosed S. pyogenes infections.[9] The risk of sepsis is relatively high compared to other bacterial infections acquired during pregnancy, and S. pyogenes is a leading cause of septic shock and death in pregnant and postpartum women.[10]
In 1928, Rebecca Lancefield published a method for serotyping S. pyogenes based on its cell-wall polysaccharide,[11] a virulence factor displayed on its surface.[12] Later, in 1946, Lancefield described the serologic classification of S. pyogenes isolates based on components of their surface pili (known as the T-antigen)[13] which are used by bacteria to attach to host cells.[14] As of 2016, a total of 120 M proteins are identified. These M proteins are encoded by 234 types emm gene with greater than 1,200 alleles.[9]
Lysogeny
All strains of S. pyogenes are polylysogenized, in that they carry one or more bacteriophage on their genomes.[15] Some of the phages may be defective, but in some cases active phage may compensate for defects in others.[16] In general, the genome of S. pyogenes strains isolated during disease are >90% identical, they differ by the phage they carry.[17]
Virulence factors
S. pyogenes has several virulence factors that enable it to attach to host tissues, evade the immune response, and spread by penetrating host tissue layers.[18] A carbohydrate-based bacterial capsule composed of hyaluronic acid surrounds the bacterium, protecting it from phagocytosis by neutrophils.[2] In addition, the capsule and several factors embedded in the cell wall, including M protein, lipoteichoic acid, and protein F (SfbI) facilitate attachment to various host cells.[19] M protein also inhibits opsonization by the alternative complement pathway by binding to host complement regulators. The M protein found on some serotypes is also able to prevent opsonization by binding to fibrinogen.[2] However, the M protein is also the weakest point in this pathogen's defense, as antibodies produced by the immune system against M protein target the bacteria for engulfment by phagocytes. M proteins are unique to each strain, and identification can be used clinically to confirm the strain causing an infection.[20]
Name
Description
Streptolysin O
An exotoxin, one of the bases of the organism's beta-hemolytic property, streptolysin O causes an immune response and detection of antibodies to it; antistreptolysin O (ASO) can be clinically used to confirm a recent infection. It is damaged by oxygen.
Streptolysin S
A cardiotoxic exotoxin, another beta-hemolytic component, not immunogenic and O2 stable: A potent cell poison affecting many types of cell including neutrophils, platelets, and subcellular organelles.
Streptococcal pyrogenic exotoxin A (SpeA)
Superantigens secreted by many strains of S. pyogenes: This streptococcal pyrogenic exotoxin is responsible for the rash of scarlet fever and many of the symptoms of streptococcal toxic shock syndrome, also known as toxic shock like syndrome (TSLS).
Streptococcal pyrogenic exotoxin C (SpeC)
Streptococcal pyrogenic exotoxin B (SpeB)
A cysteine protease and the predominant secreted protein. Multiple actions, including degrading the extracellular matrix, cytokines, complement components, and immunoglobulins. Also called streptopain.[21]
Hyaluronidase is widely assumed to facilitate the spread of the bacteria through tissues by breaking down hyaluronic acid, an important component of connective tissue. However, very few isolates of S. pyogenes are capable of secreting active hyaluronidase due to mutations in the gene that encodes the enzyme. Moreover, the few isolates capable of secreting hyaluronidase do not appear to need it to spread through tissues or to cause skin lesions.[22] Thus, the true role of hyaluronidase in pathogenesis, if any, remains unknown.
Streptodornase
Most strains of S. pyogenes secrete up to four different DNases, which are sometimes called streptodornase. The DNases protect the bacteria from being trapped in neutrophil extracellular traps (NETs) by digesting the NETs' web of DNA, to which are bound neutrophilserine proteases that can kill the bacteria.[23]
C5a peptidase cleaves a potent neutrophil chemotaxin called C5a, which is produced by the complement system.[24] C5a peptidase is necessary to minimize the influx of neutrophils early in infection as the bacteria are attempting to colonize the host's tissue.[25] C5a peptidase, although required to degrade the neutrophil chemotaxin C5a in the early stages of infection, is not required for S. pyogenes to prevent the influx of neutrophils as the bacteria spread through the fascia.[26]
Streptococcal chemokine protease
The affected tissue of patients with severe cases of necrotizing fasciitis are devoid of neutrophils.[27] The serine protease ScpC, which is released by S. pyogenes, is responsible for preventing the migration of neutrophils to the spreading infection. ScpC degrades the chemokineIL-8, which would otherwise attract neutrophils to the site of infection.[25][26]
Biofilms are a way for S. pyogenes, as well as other bacterial cells, to communicate with each other. In the biofilm gene expression for multiple purposes (such as defending against the host immune system) is controlled via quorum sensing.[34]
One of the biofilm forming pathways in GAS is the Rgg2/3 pathway. It regulates SHP's (short hydrophobic peptides) that are quorum sensing pheromones a.k.a. autoinducers. The SHP's are translated to an immature form of the pheromone and must undergo processing, first by a metalloprotease enzyme inside the cell and then in the extracellular space, to reach their mature active form. The mode of transportation out of the cell and the extracellular processing factor(s) are still unknown. The mature SHP pheromone can then be taken into nearby cells and the cell it originated from via a transmembrane protein, oligopeptide permease.[34]
In the cytosol the pheromones have two functions in the Rgg2/3 pathway. Firstly, they inhibit the activity of Rgg3 which is a transcriptional regulator repressing SHP production. Secondly, they bind another transcriptional regulator, Rgg2, that increases the production of SHP's, having an antagonistic effect to Rgg3. SHP's activating their own transcriptional activator creates a positive feedback loop, which is common for the production for quorum sensing peptides. It enables the rapid production of the pheromones in large quantities. The production of SHP's increases biofilm biogenesis.[34]
It has been suggested that GAS switches between biofilm formation and degradation by utilizing pathways with opposing effects. Whilst Rgg2/3 pathway increases biofilm, the RopB pathway disrupts it. RopB is another Rgg-like protein (Rgg1) that directly activates SpeB (Streptococcal pyrogenic exotoxin B), a cysteine protease that acts as a virulence factor. In the absence of this pathway, biofilm formation is enhanced, possibly due to the lack of the protease degrading pheromones or other Rgg2/3 pathway counteracting effects.[34]
S. pyogenes is the cause of many human diseases, ranging from mild superficial skin infections to life-threatening systemic diseases.[2] The most frequent manifestations of disease are commonly known as scarlet fever. Infections typically begin in the throat or skin. The most striking sign is a strawberry-like rash. Examples of mild S. pyogenes infections include pharyngitis (strep throat) and localized skin infection (impetigo). Erysipelas and cellulitis are characterized by multiplication and lateral spread of S. pyogenes in deep layers of the skin. S. pyogenes invasion and multiplication in the fascia beneath the skin can lead to necrotizing fasciitis, a life-threatening surgical emergency.[35][36] The bacterium is also an important cause of infection in newborns, who are susceptible to some forms of the infection that are rarely seen in adults, including meningitis.[37][38]
Like many pathogenic bacteria, S. pyogenes may colonize a healthy person's respiratory system without causing disease, existing as a commensal member of the respiratory microbiota. It is commonly found in some populations as part of the mixed microbiome of the upper respiratory tract. Individuals who have the bacterium in their bodies but no signs of disease are known as asymptomatic carriers.[39][40][41] The bacteria may start to cause disease when the host's immune system weakens, such as during a viral respiratory infection, which may lead to S. pyogenessuperinfection.[40][41]
S. pyogenes infections are commonly associated with the release of one or more bacterial toxins. The release of endotoxins from throat infections has been linked to the development of scarlet fever.[7] Other toxins produced by S. pyogenes may lead to streptococcal toxic shock syndrome, a life-threatening emergency.[2]
S. pyogenes can also cause disease in the form of post-infectious "non-pyogenic" (not associated with local bacterial multiplication and pus formation) syndromes. These autoimmune-mediated complications follow a small percentage of infections and include rheumatic fever and acute post-infectious glomerulonephritis. Both conditions appear several weeks following the initial streptococcal infection. Rheumatic fever is characterized by inflammation of the joints and/or heart following an episode of streptococcal pharyngitis. Acute glomerulonephritis, inflammation of the renal glomerulus, can follow streptococcal pharyngitis or skin infection.[citation needed]
S. pyogenes is sensitive to penicillin, and has not developed resistance to it,[42] making penicillin a suitable antibiotic to treat infections caused by this bacterium. Failure of treatment with penicillin is generally attributed to other local commensal microorganisms producing β-lactamase, or failure to achieve adequate tissue levels in the pharynx. Certain strains have developed resistance to macrolides, tetracyclines, and clindamycin.[43]
Vaccine
There is a polyvalent inactivated vaccine against several types of Streptococcus including S. pyogenes called " vacuna antipiogena polivalente BIOL" it is recommended an administration in a series of 5 weeks. Two weekly applications are made at intervals of 2 to 4 days. The vaccine is produced by the Instituto Biológico Argentino.[44]
There is another potential vaccine being developed; the vaccine candidate peptide is called StreptInCor.[45]
Applications
Bionanotechnology
Many S. pyogenes proteins have unique properties, which have been harnessed in recent years to produce a highly specific "superglue"[46][47] and a route to enhance the effectiveness of antibody therapy.[48]
Genome editing
The CRISPR system from this organism[49] that is used to recognize and destroy DNA from invading viruses, thus stopping the infection, was appropriated in 2012 for use as a genome-editing tool that could potentially alter any piece of DNA and later RNA.[50]
^ abcdeRyan KJ, Ray CG, eds. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN978-0-8385-8529-0.
^Spellerberg B, Brandt C (October 9, 2022) [Originally published September 15, 2022]. "Chapter 29: Laboratory Diagnosis of Streptococcus pyogenes (group A streptococci)". In Ferretti JJ, Stevens DL, Fischetti VA (eds.). Streptococcus pyogenes: Basic Biology to Clinical Manifestations (2nd ed.). Oklahoma City, United States: University of Oklahoma Health Sciences Center. PMID36479747. Retrieved May 11, 2023 – via National Center for Biotechnology Information, National Library of Medicine.
^ abcAndroulla E, Theresa L (February 10, 2016). "Epidemiology of Streptococcus pyogenes". Streptococcus pyogenes : Basic Biology to Clinical Manifestations. Oklahoma City, United States: University of Oklahoma Health Sciences Center. PMID26866237. Retrieved February 24, 2018.
^Tanaka H, Katsuragi S, Hasegawa J, Tanaka K, Osato K, Nakata M, et al. (January 2019). "The most common causative bacteria in maternal sepsis-related deaths in Japan were group A Streptococcus: A nationwide survey". Journal of Infection and Chemotherapy. 25 (1): 41–44. doi:10.1016/j.jiac.2018.10.004. PMID30377069.
^Pignanelli S, Brusa S, Pulcrano G, Catania MR, Cocchi E, Lanari M (October 2015). "A rare case of infant sepsis due to the emm-89 genotype of Group A Streptococcus within a community-acquired cluster". The New Microbiologica. 38 (4): 589–592. PMID26485019.
^Patterson MJ (1996). "Streptococcus". In Baron S; et al. (eds.). Streptococcus. In: Baron's Medical Microbiology (4th ed.). University of Texas Medical Branch. ISBN978-0-9631172-1-2.
^Bisno AL, Brito MO, Collins CM (April 2003). "Molecular basis of group A streptococcal virulence". The Lancet. Infectious Diseases. 3 (4): 191–200. doi:10.1016/S1473-3099(03)00576-0. PMID12679262.
^Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. (February 2006). "DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps". Current Biology. 16 (4): 396–400. Bibcode:2006CBio...16..396B. doi:10.1016/j.cub.2005.12.039. PMID16488874. S2CID667804.
^Hidalgo-Grass C, Dan-Goor M, Maly A, Eran Y, Kwinn LA, Nizet V, et al. (February 2004). "Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections". Lancet. 363 (9410): 696–703. doi:10.1016/S0140-6736(04)15643-2. PMID15001327. S2CID7219898.
^Schroeder JL, Steinke EE (December 2005). "Necrotizing fasciitis--the importance of early diagnosis and debridement". AORN Journal. 82 (6): 1031–1040. doi:10.1016/s0001-2092(06)60255-x. PMID16478083.
^"Necrotizing Fasciitis". CDC. Content source: National Center for Immunization and Respiratory Diseases, Division of Bacterial Diseases. Page maintained by: Office of the Associate Director for Communication, Digital Media Branch, Division of Public Affairs. October 26, 2017. Retrieved January 6, 2018.
^Berner R, Herdeg S, Gordjani N, Brandis M (July 2000). "Streptococcus pyogenes meningitis: report of a case and review of the literature". European Journal of Pediatrics. 159 (7): 527–529. doi:10.1007/s004310051325. PMID10923229. S2CID7693087.
Carapetis JR, Steer AC, Mulholland EK, Weber M (November 2005). "The global burden of group A streptococcal diseases". The Lancet. Infectious Diseases. 5 (11): 685–694. doi:10.1016/S1473-3099(05)70267-X. PMID16253886. (corresponding summary article)
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