| Group A Streptococcus (GAS) is a Gram-positive human pathogen that commonly causes mild skin infections. However, GAS also causes severe infections including necrotizing fasciitis. The mechanism for triggering the switch between mild and severe disease has yet to be discovered. Several groups have shown that regulation of protease production may play a role in the transition from localized to systemic infection. GAS has evolved the ability to colonize a variety of distinct host sites, and one possible mechanism for colonization is through the formation of a biofilm. A biofilm is a structured, sessile microbial community encased in an extracellular matrix and may provide protection from the immune response and antibiotic therapy. We and others have shown that GAS is able to form biofilms in vitro and in vivo, however, the regulation and role of these structures during an infection remains unclear.;We have previously shown that the streptococcal regulator of virulence (Srv) was involved in regulation of biofilm formation by regulating production of the extracellular cysteine protease SpeB. Allelic replacement of srv in the MGAS5005 background resulted in significantly decreased biofilm formation in vitro due to constitutive production of SpeB. We hypothesized that MGAS5005deltasrv would either be cleared from a subcutaneous infection due to the inability to form a biofilm or constitutive SpeB production would elicit more localized damage. Our results supported the latter hypothesis, and increased lesion development was associated with detectable levels of SpeB and decreased biofilm formation and in the tissue. Genetic and chemical inactivation of speB/SpeB in MGAS5005deltasrv restored biofilm formation and reduced lesion formation to wild-type levels, supporting our hypothesis that the increased tissue damage was due to SpeB.;MGAS5005 has a naturally occurring mutation in the sensor kinase domain (CovS) of the two component regulatory system CovRS. speB is normally repressed by CovR in the absence of CovS, which lead us to the hypothesis that Srv regulation of SpeB is a covS-independent event. Invasive clinical isolates with covS intact also produced decreased biofilms due to increased SpeB production. Our results suggest that Srv regulation of SpeB is independent of CovRS and this may be one mechanism for regulating biofilm dispersal during disease. |
