Genome-Wide Analysis of Group A Streptococci Reveals a Mutation That Modulates Global Phenotype and Disease Specificity

Abstract

Many human pathogens produce phenotypic variants as a means to circumvent the host immune system and enhance survival and, as a potential consequence, exhibit increased virulence. For example, it has been known for almost 90 y that clinical isolates of the human bacterial pathogen group A streptococci (GAS) have extensive phenotypic heterogeneity linked to variation in virulence. However, the complete underlying molecular mechanism(s) have not been defined. Expression microarray analysis of nine clinical isolates identified two fundamentally different transcriptomes, designated pharyngeal transcriptome profile (PTP) and invasive transcriptome profile (ITP). PTP and ITP GAS differed in approximately 10% of the transcriptome, including at least 23 proven or putative virulence factor genes. ITP organisms were recovered from skin lesions of mice infected subcutaneously with PTP GAS and were significantly more able to survive phagocytosis and killing by human polymorphonuclear leukocytes. Complete genome resequencing of a mouse-derived ITP GAS revealed that the organism differed from its precursor by only a 7-bp frameshift mutation in the gene (covS) encoding the sensor kinase component of a two-component signal transduction system implicated in virulence. Genetic complementation, and sequence analysis of covR/S in 42 GAS isolates confirmed the central role of covR/S in transcriptome, exoproteome, and virulence modulation. Genome-wide analysis provides a heretofore unattained understanding of phenotypic variation and disease specificity in microbial pathogens, resulting in new avenues for vaccine and therapeutics research.

No increased risk of valvular heart disease in adult poststreptococcal reactive arthritis

“…Traditionally this "rheumatogenecity" has been considered to be a feature of strains belonging to certain M serotypes (the serotypes M3 and M18 have been related to ARF). Recent genome-wide analyses of group A streptococci have demonstrated that the heterogeneity in disease severity caused by group A streptococci is mediated by genetic variation in a signal transduction system that affects the expression of virulence factors (36,37). The combination of a susceptible host and a virulent group A Streptococcus may induce an exaggerated immune response, leading to valvular heart disease.…”

DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection

“…The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome 1 . Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad spectrum cysteine protease (SpeB) 2,3 and allowing the recruitment and activation of host plasminogen on the bacterial surface 4 . Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps (NETs) 5,6 , serves as a selective force for covRS mutation.…”

“…In the M1T1 GAS clone, the transition from local to systemic infection can be linked to mutations in the two-component covRS regulator. The effect of these mutations is a distinct shift in the transcriptional profile of invasive GAS isolates compared to mucosal (throat) isolates 3 . The covRS mutation and changes in gene expression are recapitulated upon subcutaneous challenge of mice and analysis of GAS disseminating to the spleen in comparison with those in the original inocolum 3 .…”

Impact of contusion injury on intramuscular emm1 group a streptococcus infection and lymphatic spread

“…To determine the basis for hyper-encapsulation, in one experiment, we undertook genome sequencing of representative isolates from lymph node and spleen from a single mouse. Although isolates from the spleen demonstrated a mutation in covR , which might be predicted from many other studies [9,32], the hyper-encapsulated GAS variants in the draining lymph node demonstrated a deletion in the hasABC promoter which leads to loss of one of the reported CovR binding sites[25], thereby de-repressing capsule production specifically [25]. The hyper-encapsulated promoter mutant strain (P2) had enhanced fitness with regard to transit to, and/or retention in, the draining lymph node consistent with the reported interaction between hyaluronan and the lymphatic receptor LYVE-1 [22].…”

“…One of the most-studied two component GAS regulatory systems is CovRS, which is responsible for regulating 10–15% of the GAS genome, and repressing the expression of virulence genes such as those of the hasABC operon that result in expression of hyaluronan capsule [8]. CovRS plays an important role in the systemic dissemination of GAS and spontaneous mutations have been demonstrated in hyper-encapsulated emm 1 GAS isolates from spleen during experimental in vivo infection [9,10]. …”