The Signal Recognition Particle Pathway Is Required for Virulence in Streptococcus pyogenes

Abstract

The signal recognition particle (SRP) pathway is a universally conserved pathway for targeting polypeptides for secretion via the cotranslational pathway. In particular, the SRP pathway is thought to be the main mechanism for targeting polypeptides in gram-positive bacteria, including a number of important human pathogens. Though widely considered to be an essential cellular component, recent advances have indicated this pathway may be dispensable in gram-positive bacteria of the genus Streptococcus under in vitro conditions. However, its importance for the pathogenesis of streptococcal disease is unknown. In this study, we investigated the importance of the SRP pathway for virulence factor secretion in the human pathogen Streptococcus pyogenes. While the SRP pathway was not found to be essential for viability in vitro, SRP mutants demonstrated a medium-specific growth defect that could be rescued by the addition of glucose. We also observed that a distinct subset of virulence factors were dependent upon the SRP pathway for secretion, whereas others were completely independent of this pathway. Significantly, deletion of the SRP pathway resulted in mutants that were highly attenuated in both a zebrafish model of necrotic myositis and a murine subcutaneous ulcer model, highlighting the importance of this pathway in vivo. These studies emphasize the importance of the SRP pathway for the in vivo survival and pathogenesis of S. pyogenes.

The 4.5S RNA component of the signal recognition particle is required for group A Streptococcus virulence

“…Thus, the 4.5S RNA is not an essential gene in GAS. Similar to results observed following ffh mutation (Rosch et al, 2008), mutation of the gene encoding 4.5S RNA did not appreciably affect growth yield compared to the parental strain following growth in THY broth, but did increase the doubling time from 52 min for MGAS2221 to 75 min for 2221D4.5S (Fig. 1c).…”

“…As was observed in S. mutans, the GAS ffh mutant gave growth yields similar to those of the parental strain when grown in nutrient-rich media but with an increased doubling time. Growth of the ffh mutant strain was identified as being glucose-dependent, with a severe reduction in growth rate and yield in media containing low concentrations of glucose (Rosch et al, 2008). In addition to ffh mutation resulting in mediumspecific growth defects, the secreted virulence factors NADglycohydrolase and streptolysin O were present at lower concentrations in the supernatant of the ffh mutant strain, and the growth-phase expression of the secreted protease SpeB was deregulated.…”

“…Recently, it was determined that the ffh gene is not essential in GAS (Rosch et al, 2008). To identify whether the same was true for the RNA component of the SRP particle we set out to create an isogenic 4.5S RNA mutant derivative of GAS isolate MGAS2221.…”

“…In addition to ffh mutation resulting in mediumspecific growth defects, the secreted virulence factors NADglycohydrolase and streptolysin O were present at lower concentrations in the supernatant of the ffh mutant strain, and the growth-phase expression of the secreted protease SpeB was deregulated. Importantly, the ffh mutant strain was severely attenuated in its ability to cause disease in a zebrafish model of necrotic myositis and a murine model of soft tissue infection (Rosch et al, 2008). Here, we investigate the 4.5S RNA-encoding gene and show that it is also a non-essential gene in GAS.…”

“…Characterization of the SRP pathway in GAS has thus far been limited to a study that focused on the ffh gene (Rosch et al, 2008). An ffh mutant GAS strain was successfully constructed, showing that the SRP pathway was not essential in this pathogen.…”