Partial loss of CovS function in Streptococcus pyogenes causes severe invasive disease

BACKGROUND: CovRS (or CsrRS) is a two-component regulatory system that regulates the production of multiple virulence factors in Streptococcus pyogenes. covS mutations are often found in isolates recovered from mice that have been experimentally infected with S. pyogenes and covS mutations enhance bacterial virulence in an invasive infection mouse model. In addition, covS mutations were detected more frequently in a panel of clinical isolates from severe invasive streptococcal infections than those from non-severe infections. Thus, covS mutations may be associated with the onset of severe invasive infections. RESULTS: Known covS mutations were divided into two groups: (i) frameshift mutations that caused a deletion of functional regions and (ii) point mutations that caused single (or double) amino acid(s) substitutions. Frameshift mutations are frequent in mouse-passaged isolates, whereas point mutations are frequent in clinical isolates. The functions of CovS proteins with a single amino acid substitution in clinical isolates were estimated based on the streptococcal pyrogenic exotoxin B (SpeB) production and NAD(+)-glycohydrolase (NADase) activity, which are known to be regulated by the CovRS system. Point mutations partially, but not completely, impaired the function of the covS alleles. We also investigated some of the benefits that a partial loss of function in covS alleles with point mutations might confer on clinical isolates. We found that covS knockout mutants (ΔcovS strains) had an impaired growth ability in a normal atmosphere in Todd Hewitt broth compared with parental isolates having wild-type or point-mutated covS. CONCLUSIONS: The loss of CovS proteins in S. pyogenes may confer greater virulence, but bacteria may also lose the ability to respond to certain external signals recognized by CovS. Therefore, point mutations that retain the function of CovS and confer hypervirulence may have natural selective advantages.