Genetic Switch to Hypervirulence Reduces Colonization Phenotypes of the Globally Disseminated Group AStreptococcusM1T1 Clone

Abstract

Background The recent resurgence of invasive group A streptococcal disease has been paralleled by the emergence of the M1T1 clone. Recently, invasive disease initiation to has been linked to mutations in the covR/S two-compnent regulator. Here we investigate if a fitness cost is associated with covS mutation that counterbalances hypervirulence. Methods Wild-type M1T1 GAS and an isogenic covS mutant derived from animal passage were compared for adherence to human laryngeal epithelial cells, keratinocytes or fibronectin, biofilm formation, and binding to intact mouse skin. Targeted mutagenesis of capsule expression from both strains was performed for analysis of its unique contribution to the observed phenotypes. Results The covS mutant bacteria showed reduced capacity to bind to epithelial cell layers as a consequence of increased capsule expression. The covS mutant strain also had reduced capacity to bind fibronectin and to form biofilms on plastic and epithelial cell layers. A defect in skin adherence of the covS mutant strain was demonstrated in a murine model. Conclusions Reduced colonization capacity provides a potential explanation as to why the covS mutation conferring hypervirulence has not become fixed in the globally-disseminated M1T1 GAS clone, but rather may arise anew under innate immune selection in individual patients.

Hyaluronan Breakdown Contributes to Immune Defense against Group A Streptococcus

“…However, CD44 has also been reported to serve as a receptor for GAS adherence to keratinocytes (29) and pharyngeal epithelial cells (30) and may therefore participate in GAS virulence. Indeed, the GAS HA capsule impairs keratinocyte (29,31) and macrophage (32) uptake of the pathogen and aids biofilm formation (31). In our comparison of CD44 Ϫ/Ϫ and WT mice, we saw evidence for both functions.…”

CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants

“…Notably, a comparative study of GAS gene expression (12) in vitro versus in vivo revealed that an enriched set of genes, including genes involved in metabolic activities, were differentially expressed in response to environmental adaptation between wild-type (WT) GAS M1T1 and its CovS Ϫ mutant. These results suggested that CovRS globally regulates virulence determinants by rapidly switching the genotypes of GAS but also appropriately remodels the metabolic system in response to diverse environmental stresses to ensure bacterial survival in hostile host environments (4,12).…”

Re-emergence of scarlet fever: old players return?

“…No covRS two-component system mutation was found in the sequenced isolates; this is not surprising since several authors suggest covRS to be related to invasive GAS infections, such as necrotizing fasciitis rather than pharyngitis [4,11,15]. These mobile genetic elements represented more than 80% of scarlet fever isolates associated with the outbreak.…”

“…It is hypothesized that this phenomenon is due to microbial determinants, such as new strains with higher virulence capacities. This could come from the acquisition by Horizontal Gene Transfer of mobile genetic elements carrying superantigenic virulence factors and antimicrobial resistance determinants, or from newly acquired mutations of virulence regulators, such as the two component covRS operon, in the M1T1 strain 5448 (although this very mutation was also shown to decrease colonization and thus probably transmissibility) [3,4]. It is likely that environmental and host-related factors are also involved.…”