Subsystem: Streptococcus pyogenes recombinatorial zone

This subsystem's description is:

This subsystem describes a group A streptococcal genomic region that is highly recombinatorial between closely related strains, and has been shown to play a crucial role in pili-production and adhesion to human tissues.

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This subsystem describes a group A streptococcal genomic region that is highly recombinatorial between closely related strains, and has been shown to play a crucial role in pili-production and adhesion to human tissues.
This subsystem is built based on the following publication:


Genomic localization of a T serotype locus to a recombinatorial zone encoding extracellular matrix-binding proteins in Streptococcus pyogenes.
Bessen DE, Kalia A.
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

"Streptococcus pyogenes is an important bacterial pathogen afflicting humans. A striking feature is its extraordinary biological diversity, evident in the wide range of diseases it can cause and the antigenic heterogeneity present on its surface. The T antigens form the basis of a major serological typing scheme that is often used as an alternative or supplement to M typing. Unlike M typing, the genetic basis for T typing is poorly understood. In this report, the tee6 gene is localized to a position approximately equal to 3.3 kb downstream from prtF1 (or sfbI), which encodes the Fn-binding protein, protein F, a key virulence factor. Comparison of this portion of the genome with those of four additional strains reveals the presence of genes encoding a collagen-binding protein (Cpa) and a second Fn-binding protein (PrtF2 or PfbpI). This chromosomal region--here designated the FCT region--is approximately 11 to 16 kb in length and is flanked at both ends by long stretches of highly conserved sequence. For each of the five strains, the FCT region contains a unique combination of semiconserved loci, indicative of extensive intergenomic recombination. The data provide evidence that the highly recombinatorial FCT region of the S. pyogenes genome is under strong selection for change in response to the host environment.

Protein F/ cpa??
There are two alleles of the fibronectin-binding protein (prtF, prtF2), and in many instances they both co-exist in one genome. In some strains, a close homolog of prtF is the collagen-binding adhesin (cpa).

RALPs (RofA-like proteins)
There are 4 classes of RALPs, most prominent of which are RofA and Nra.
RofA (The regulator of protein F) and Nra (Negative transcriptional regulator) share 60% amino acid identity, but are thought to be of opposite function. While RofA is a positive regulator, Nra is a negative regulator that suppresses its own transcription.

Read Characterization of nra, a global negative regulator gene in group A streptococci.
Group A streptococcal RofA-type global regulators exhibit a strain-specific genomic presence and regulation pattern.

Kreikemeyer B, Beckert S, Braun-Kiewnick A, Podbielski A.

Department of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Schillingallee 70, D-18055 Rostock, Germany.

RofA-like protein (RALP) type regulators have been shown to exist in different forms in group A streptococci (GAS) and to regulate the expression of important bacterial adhesins. This study shows that the vast majority of strains from different GAS M serotypes carried a rofA virulence regulator gene in their genome and that this gene could be detected in combination with other RALP genes and RALP-dependent adhesin genes in a strain-specific manner. The gene encoding the Nra regulator was predominantly found in opacity factor (OF)-negative serotypes. When analysing a rofA mutant in a serotype M2 strain, the strain specificity was also found in the positive and negative regulatory functions of RALP genes as well as in the type and number of virulence genes and functions controlled by the RALP genes. Of 17 virulence-associated genes tested, only one, the putative streptolysin S gene, was observed to be derepressed in RALP mutants of three different GAS serotype strains. This strain-specific variability of RALP regulon sizes is associated with different patterns of host cell attachment and internalization. In addition, RofA2 was shown to control expression of the ribosomal protein gene rpsL. As a consequence, it was demonstrated for the first time in streptococci that aminoglycoside resistance mediated by rpsL expression is apparently controlled by a virulence gene regulator.

Finally, the importance of MSMRL in regulation of virulence in S. pyogenes is outlined in the following paper:
MsmR, a specific positive regulator of the Streptococcus pyogenes FCT pathogenicity region and cytolysin-mediated translocation system genes.
Nakata M, Podbielski A, Kreikemeyer B.

Department of Medical Microbiology and Hospital Hygiene, Hospital of the Rostock University, Schillingallee 70, 18057 Rostock, Germany.

As a prerequisite for colonization or causing local infections, Streptococcus pyogenes (group A streptococci, GAS) need to specifically adhere to eukaryotic cell surfaces. Predominantly responsible adhesin genes are contained in a genotype-specific pattern within the FCT region of the GAS genome. In this study, MsmR, belonging to AraC/XylS type transcriptional regulators, was identified in the FCT region as a positive regulator of the major fibronectin-binding adhesin protein F2 in a serotype M49 strain. Compared with the wild-type strain, the msmR mutant showed reduced binding to immobilized fibronectin and decreased adherence to and internalization into human pharyngeal epithelial cells. These results suggested that altered levels of fibronectin-binding proteins in the mutant affect eukaryotic cell attachment and internalization. Complete transcriptome and reporter fusion assay data revealed that MsmR positively regulates FCT region genes including Nra and cytolysin-mediated translocation system genes. Consistent with the genetic data, the mutant showed attenuated streptolysin O activity and eukaryotic cell cytotoxity. Direct binding of recombinant MsmR to nga, nra/cpa and prtF2 promoter regions was confirmed by EMSA assays. As prior analysis demonstrated the Nra regulator negatively affects gene expression from the FCT region, MsmR and Nra appear to adversely control crucial virulence factor expression in GAS and thus contribute to a fine-tuned balance between local destructive process and metastatic spreading of the bacteria.