Editing Streptococcus pyogenes (section)

==Bacteriology==
[[File:Streptococcus Pyogenes (Group A Strep) (52606801786).jpg|thumb|False-color [[scanning electron microscope]] image of ''Streptococcus pyogenes'' (orange) during [[phagocytosis]] with a human [[neutrophil]] (blue)]]

=== Serotyping ===

In 1928, [[Rebecca Lancefield]] published a method for serotyping ''S. pyogenes'' based on its cell-wall polysaccharide,<ref name=Pignanelli_2015>{{cite journal | vauthors = Pignanelli S, Brusa S, Pulcrano G, Catania MR, Cocchi E, Lanari M | title = A rare case of infant sepsis due to the emm-89 genotype of Group A Streptococcus within a community-acquired cluster | journal = The New Microbiologica | volume = 38 | issue = 4 | pages = 589–592 | date = October 2015 | pmid = 26485019 }}</ref> a [[virulence]] factor displayed on its surface.<ref name=Lancefield_1928>{{cite journal | vauthors = Lancefield RC | title = The Antigenic Complex of Streptococcus Hæmolyticus | journal = The Journal of Experimental Medicine | volume = 47 | issue = 1 | pages = 91–103 | date = January 1928 | pmid = 19869404 | pmc = 2131344 | doi = 10.1084/jem.47.1.91 }}</ref> Later, in 1946, Lancefield described the serologic classification of ''S. pyogenes'' isolates based on components of their surface [[pilus|pili]] (known as the T-antigen)<ref name=Lancefield_1946>{{cite journal | vauthors = Lancefield RC, Dole VP | title = The Properties of T Antigens Extracted from Group a Hemolytic Streptococci | journal = The Journal of Experimental Medicine | volume = 84 | issue = 5 | pages = 449–471 | date = October 1946 | pmid = 19871581 | pmc = 2135665 | doi = 10.1084/jem.84.5.449 }}</ref>  which are used by bacteria to attach to host cells.<ref name=Mora_2005>{{cite journal | vauthors = Mora M, Bensi G, Capo S, Falugi F, Zingaretti C, Manetti AG, Maggi T, Taddei AR, Grandi G, Telford JL | display-authors = 6 | title = Group A Streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 43 | pages = 15641–15646 | date = October 2005 | pmid = 16223875 | pmc = 1253647 | doi = 10.1073/pnas.0507808102 | doi-access = free | bibcode = 2005PNAS..10215641M }}</ref> As of 2016, a total of 120 [[M protein (Streptococcus)|M proteins]] have been identified. These M proteins are encoded by 234 type ''emm'' genes with greater than 1,200 alleles.<ref name="epidemiology"/>

=== Lysogeny ===

All strains of ''S. pyogenes'' are polylysogenized, in that they carry one or more [[bacteriophage]] in their genomes.<ref name="Ferretti_2001">{{cite journal | vauthors = Ferretti JJ, McShan WM, Ajdic D, Savic DJ, Savic G, Lyon K, Primeaux C, Sezate S, Suvorov AN, Kenton S, Lai HS, Lin SP, Qian Y, Jia HG, Najar FZ, Ren Q, Zhu H, Song L, White J, Yuan X, Clifton SW, Roe BA, McLaughlin R | display-authors = 6 | title = Complete genome sequence of an M1 strain of Streptococcus pyogenes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 8 | pages = 4658–4663 | date = April 2001 | pmid = 11296296 | pmc = 31890 | doi = 10.1073/pnas.071559398 | doi-access = free | bibcode = 2001PNAS...98.4658F }}</ref> Some of the phages may be defective, but in some cases active phage may compensate for defects in others.<ref name="Canchaya_2002">{{cite journal | vauthors = Canchaya C, Desiere F, McShan WM, Ferretti JJ, Parkhill J, Brüssow H | title = Genome analysis of an inducible prophage and prophage remnants integrated in the Streptococcus pyogenes strain SF370 | journal = Virology | volume = 302 | issue = 2 | pages = 245–258 | date = October 2002 | pmid = 12441069 | doi = 10.1006/viro.2002.1570 | doi-access = free }}</ref> In general, the genome of ''S. pyogenes'' strains isolated during disease are >90% identical, they differ by the phage they carry.<ref name="Banks_2003">{{cite journal | vauthors = Banks DJ, Porcella SF, Barbian KD, Martin JM, Musser JM | title = Structure and distribution of an unusual chimeric genetic element encoding macrolide resistance in phylogenetically diverse clones of group A Streptococcus | journal = The Journal of Infectious Diseases | volume = 188 | issue = 12 | pages = 1898–1908 | date = December 2003 | pmid = 14673771 | doi = 10.1086/379897 | doi-access = free }}</ref>

=== Virulence factors ===

''S. pyogenes'' has several [[virulence factor]]s that enable it to attach to host tissues, evade the immune response, and spread by penetrating host tissue layers.<ref name="Baron">{{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.824|title=Streptococcus. ''In:'' Baron's Medical Microbiology|author=Patterson MJ|publisher=University of Texas Medical Branch|year=1996|isbn=978-0-9631172-1-2|editor=Baron S|edition=4th|display-editors=etal|chapter=Streptococcus}}</ref>  A carbohydrate-based [[bacterial capsule]] composed of [[hyaluronic acid]] surrounds the bacterium, protecting it from [[phagocytosis]] by [[neutrophils]].<ref name="Sherris" /> In addition, the capsule and several factors embedded in the cell wall, including [[M protein (Streptococcus)|M protein]], [[lipoteichoic acid]], and protein F (SfbI) facilitate attachment to various host cells.<ref name="Bisno_2003">{{cite journal | vauthors = Bisno AL, Brito MO, Collins CM | title = Molecular basis of group A streptococcal virulence | journal = The Lancet. Infectious Diseases | volume = 3 | issue = 4 | pages = 191–200 | date = April 2003 | pmid = 12679262 | doi = 10.1016/S1473-3099(03)00576-0 }}</ref>  M protein also inhibits [[opsonization]] by the alternative [[complement system|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]].<ref name="Sherris" />  However, the M protein is also the weakest point in this pathogen's defense, as [[Antibody|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.<ref>{{cite journal | vauthors = Engel ME, Muhamed B, Whitelaw AC, Musvosvi M, Mayosi BM, Dale JB | title = Group A streptococcal emm type prevalence among symptomatic children in Cape Town and potential vaccine coverage | journal = The Pediatric Infectious Disease Journal | volume = 33 | issue = 2 | pages = 208–210 | date = February 2014 | pmid = 23934204 | pmc = 3947201 | doi = 10.1097/INF.0b013e3182a5c32a }}</ref>

{| class="wikitable" font-size:85%; margin-left:15px"
|-
!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 O<sub>2</sub> stable: A potent cell poison affecting many types of cell including neutrophils, platelets, and subcellular organelles.
|-
|Streptococcal pyrogenic exotoxin A (SpeA)
|rowspan=2|[[Superantigen]]s 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]].<ref>{{cite journal | vauthors = Nelson DC, Garbe J, Collin M | title = Cysteine proteinase SpeB from Streptococcus pyogenes - a potent modifier of immunologically important host and bacterial proteins | journal = Biological Chemistry | volume = 392 | issue = 12 | pages = 1077–1088 | date = December 2011 | pmid = 22050223 | doi = 10.1515/BC.2011.208 | s2cid = 207441558 | doi-access = free }}</ref>
|-
|[[Streptokinase]]
|Enzymatically activates [[plasminogen]], a proteolytic enzyme, into [[plasmin]], which in turn digests [[fibrin]] and other proteins
|-
|[[Hyaluronidase]]
|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.<ref name=Starr_2006>{{cite journal | vauthors = Starr CR, Engleberg NC | title = Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus | journal = Infection and Immunity | volume = 74 | issue = 1 | pages = 40–48 | date = January 2006 | pmid = 16368955 | pmc = 1346594 | doi = 10.1128/IAI.74.1.40-48.2006 }}</ref>  Thus, the true role of hyaluronidase in pathogenesis, if any, remains unknown.
|-
|Streptodornase
|Most strains of ''S. pyogenes'' secrete up to four different [[DNase]]s, 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 [[neutrophil]] [[serine protease]]s that can kill the bacteria.<ref name=Buchanan_2006>{{cite journal | vauthors = Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V | display-authors = 6 | title = DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps | journal = Current Biology | volume = 16 | issue = 4 | pages = 396–400 | date = February 2006 | pmid = 16488874 | doi = 10.1016/j.cub.2005.12.039 | bibcode = 2006CBio...16..396B | s2cid = 667804 }}</ref>
|-
|[[Complement component 5a|C5a]] [[peptidase]]
|C5a peptidase cleaves a potent [[neutrophil]] chemotaxin called [[Complement component 5a|C5a]], which is produced by the [[complement system]].<ref name=Wexler_1985>{{cite journal | vauthors = Wexler DE, Chenoweth DE, Cleary PP | title = Mechanism of action of the group A streptococcal C5a inactivator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 23 | pages = 8144–8148 | date = December 1985 | pmid = 3906656 | pmc = 391459 | doi = 10.1073/pnas.82.23.8144 | doi-access = free | bibcode = 1985PNAS...82.8144W }}</ref>  C5a peptidase is necessary to minimize the influx of [[neutrophil]]s early in infection as the bacteria are attempting to colonize the host's tissue.<ref name="Ji 1996">{{cite journal | vauthors = Ji Y, McLandsborough L, Kondagunta A, Cleary PP | title = C5a peptidase alters clearance and trafficking of group A streptococci by infected mice | journal = Infection and Immunity | volume = 64 | issue = 2 | pages = 503–510 | date = February 1996 | pmid = 8550199 | pmc = 173793 | doi = 10.1128/IAI.64.2.503-510.1996 }}</ref> 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]].<ref name="Hidalgo-Grass 2006">{{cite journal | vauthors = Hidalgo-Grass C, Mishalian I, Dan-Goor M, Belotserkovsky I, Eran Y, Nizet V, Peled A, Hanski E | display-authors = 6 | title = A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues | journal = The EMBO Journal | volume = 25 | issue = 19 | pages = 4628–4637 | date = October 2006 | pmid = 16977314 | pmc = 1589981 | doi = 10.1038/sj.emboj.7601327 }}</ref>
|-
|Streptococcal chemokine protease
|The affected tissue of patients with severe cases of [[necrotizing fasciitis]] are devoid of neutrophils.<ref name=Hidalgo-Grass_2004>{{cite journal | vauthors = Hidalgo-Grass C, Dan-Goor M, Maly A, Eran Y, Kwinn LA, Nizet V, Ravins M, Jaffe J, Peyser A, Moses AE, Hanski E | display-authors = 6 | title = Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections | journal = Lancet | volume = 363 | issue = 9410 | pages = 696–703 | date = February 2004 | pmid = 15001327 | doi = 10.1016/S0140-6736(04)15643-2 | s2cid = 7219898 }}</ref> 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 [[chemokine]] [[Interleukin 8|IL-8]], which would otherwise attract [[neutrophil]]s to the site of infection.<ref name="Ji 1996"/><ref name="Hidalgo-Grass 2006"/>
|-
|}

=== Genome ===
The genomes of different strains were sequenced (genome size is 1.8–1.9 Mbp),<ref>{{cite journal | vauthors = Beres SB, Richter EW, Nagiec MJ, Sumby P, Porcella SF, DeLeo FR, Musser JM | title = Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 18 | pages = 7059–7064 | date = May 2006 | pmid = 16636287 | pmc = 1459018 | doi = 10.1073/pnas.0510279103 | doi-access = free | bibcode = 2006PNAS..103.7059B }}</ref> encoding about 1700-1900 proteins (1700 in strain NZ131,<ref>{{cite web|url=http://microbesonline.org/cgi-bin/genomeInfo.cgi?tId=471876|title=Streptococcus pyogenes NZ131}}</ref><ref name="McShan2008">{{cite journal | vauthors = McShan WM, Ferretti JJ, Karasawa T, Suvorov AN, Lin S, Qin B, Jia H, Kenton S, Najar F, Wu H, Scott J, Roe BA, Savic DJ | display-authors = 6 | title = Genome sequence of a nephritogenic and highly transformable M49 strain of Streptococcus pyogenes | journal = Journal of Bacteriology | volume = 190 | issue = 23 | pages = 7773–7785 | date = December 2008 | pmid = 18820018 | pmc = 2583620 | doi = 10.1128/JB.00672-08 }}</ref> 1865 in strain MGAS5005<ref name="Sumby">{{cite journal | vauthors = Sumby P, Porcella SF, Madrigal AG, Barbian KD, Virtaneva K, Ricklefs SM, Sturdevant DE, Graham MR, Vuopio-Varkila J, Hoe NP, Musser JM | display-authors = 6 | title = Evolutionary origin and emergence of a highly successful clone of serotype M1 group a Streptococcus involved multiple horizontal gene transfer events | journal = The Journal of Infectious Diseases | volume = 192 | issue = 5 | pages = 771–782 | date = September 2005 | pmid = 16088826 | doi = 10.1086/432514 | doi-access = free }}</ref><ref>{{cite web|url=http://microbesonline.org/cgi-bin/genomeInfo.cgi?tId=293653|title=Streptococcus pyogenes MGAS5005}}</ref>). Complete genome sequences of the type strain of ''S. pyogenes'' ([https://www.phe-culturecollections.org.uk/products/bacteria/detail.jsp?refId=NCTC+8198&collection=nctc NCTC 8198<sup>T</sup>] = [https://ccug.se/strain?id=4207&s=0&p=1&sort=rel&collection=entire&records=25&t=4207 CCUG 4207<sup>T</sup>]) are available in [[DNA Data Bank of Japan]], [[European Nucleotide Archive]], and [[GenBank]] under the accession numbers [https://www.ncbi.nlm.nih.gov/nuccore/NZ_LN831034.1 LN831034] and [https://www.ncbi.nlm.nih.gov/nuccore/NZ_CP028841.1 CP028841].<ref>{{cite journal | vauthors = Salvà-Serra F, Jaén-Luchoro D, Jakobsson HE, Gonzales-Siles L, Karlsson R, Busquets A, Gomila M, Bennasar-Figueras A, Russell JE, Fazal MA, Alexander S, Moore ER | display-authors = 6 | title = Complete genome sequences of Streptococcus pyogenes type strain reveal 100%-match between PacBio-solo and Illumina-Oxford Nanopore hybrid assemblies | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 11656 | date = July 2020 | pmid = 32669560 | pmc = 7363880 | doi = 10.1038/s41598-020-68249-y }}</ref>

=== Biofilm formation ===
[[Biofilm]]s 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]].<ref name="pmid21829369">{{cite journal | vauthors = Chang JC, LaSarre B, Jimenez JC, Aggarwal C, Federle MJ | title = Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development | journal = PLOS Pathogens | volume = 7 | issue = 8 | pages = e1002190 | date = August 2011 | pmid = 21829369 | pmc = 3150281 | doi = 10.1371/journal.ppat.1002190 | doi-access = free }}</ref> 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.<ref name="pmid21829369"/> 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.<ref name="pmid21829369"/> 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.<ref name="pmid21829369"/>