In silico characterisation of the two-component system regulators of Streptococcus pyogenes.

Sean J Buckley,David J Mcmillan,Mark R Davies,Peter Timms,Benfang Lei

doi:10.1371/journal.pone.0199163

Abstract

Bacteria respond to environmental changes through the co-ordinated regulation of gene expression, often mediated by two-component regulatory systems (TCS). Group A Streptococcus (GAS), a bacterium which infects multiple human body sites and causes multiple diseases, possesses up to 14 TCS. In this study we examined genetic variation in the coding sequences and non-coding DNA upstream of these TCS as a method for evaluating relationships between different GAS emm-types, and potential associations with GAS disease. Twelve of the 14 TCS were present in 90% of the genomes examined. The length of the intergenic regions (IGRs) upstream of TCS coding regions varied from 39 to 345 nucleotides, with an average nucleotide diversity of 0.0064. Overall, IGR allelic variation was generally conserved with an emm-type. Subsequent phylogenetic analysis of concatenated sequences based on all TCS IGR sequences grouped genomes of the same emm-type together. However grouping with emm-pattern and emm-cluster-types was much weaker, suggesting epidemiological and functional properties associated with the latter are not due to evolutionary relatedness of emm-types. All emm5, emm6 and most of the emm18 genomes, all historically considered rheumatogenic emm-types clustered together, suggesting a shared evolutionary history. However emm1, emm3 and several emm18 genomes did not cluster within this group. These latter emm18 isolates were epidemiologically distinct from other emm18 genomes in study, providing evidence for local variation. emm-types associated with invasive disease or nephritogenicity also did not cluster together. Considering the TCS coding sequences (cds), correlation with emm-type was weaker than for the IGRs, and no strong correlation with disease was observed. Deletion of the malate transporter, maeP, was identified that serves as a putative marker for the emm89.0 subtype, which has been implicated in invasive outbreaks. A recombination-related, subclade-forming DNA motif was identified in the putative receiver domain of the Spy1556 response regulator that correlated with throat-associated emm-pattern-type A-C strains.

Highlights

Streptococcus pyogenes (Group A Streptococcus, GAS) is a human pathogen responsible for a suite of human diseases that vary in both symptom and severity [1]
Deletion of the malate transporter, maeP, was identified that serves as a putative marker for the emm89.0 subtype, which has been implicated in invasive outbreaks
Characterisation of regulatory genes in S. pyogenes types to cause acute rheumatic fever (ARF)/rheumatic heart disease (RHD) are likely found in the core genome of these emm-types, and may have been vertically inherited from a common ancestor

Summary

Introduction

Streptococcus pyogenes (Group A Streptococcus, GAS) is a human pathogen responsible for a suite of human diseases that vary in both symptom and severity [1]. Potential sequelae of GAS infection include post streptococcal glomerulonephritis (PSGN), acute rheumatic fever (ARF), and rheumatic heart disease (RHD) [2]. A subset of these emm-types (for example emm, emm, and more recently emm89) are strongly associated with invasive disease outbreaks in Europe and North America, suggesting that genetic determinants that differ between emm-types, and even within emm-types have a role in determining the relative pathogenicity of an emm-type [6, 7]. ARF and RHD are autoimmune sequelae that can follow untreated pharyngeal GAS infection [8], and the leading cause of GAS related mortality. A subset of GAS M-serotypes (for example, emm, emm and emm6) have been considered as ‘rheumatogenic’ GAS emm-types [9, 10], having stronger association with ARF/ RHD than other strains. As epidemiological studies of streptococcal disease in developing nations routinely fail to report the presence of traditional ‘rheumatogenic’ emmtypes, this concept is being re-examined. [11,12,13,14]

Methods

Results

Discussion

Conclusion