CovS Simultaneously Activates and Inhibits the CovR-Mediated Repression of Distinct Subsets of Group A Streptococcus Virulence Factor-Encoding Genes

Abstract

To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A Streptococcus (GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS). covR and covS mutant strains arise spontaneously during invasive infections and, in in vivo models of infection, rapidly become dominant. Here, we compared wild-type GAS with covR, covS, and covRS isogenic mutant strains to investigate the heterogeneity in the types of natural mutations that occur in covR and covS and the phenotypic consequences of covR or covS mutation. We found that the response regulator CovR retains some regulatory function in the absence of CovS and that CovS modulates CovR to significantly enhance repression of one group of genes (e.g., the speA, hasA, and ska genes) while it reduces repression of a second group of genes (e.g., the speB, grab, and spd3 genes). We also found that different in vivo-induced covR mutations can lead to strikingly different transcriptomes. While covS mutant strains show increased virulence in several invasive models of infection, we determined that these mutants are significantly outcompeted by wild-type GAS during growth in human saliva, an ex vivo model of upper respiratory tract infection. We propose that CovS-mediated regulation of CovR activity plays an important role in the ability of GAS to cycle between pharyngeal and invasive infections.

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

“…The changes in transcript abundance following 4.5S RNA mutation are the reverse of that observed following mutation of covS (control of virulence Sensor; also known as csrS), which encodes the membrane-spanning sensor kinase component of the CovR/S two-component system (Bernish & van de Rijn, 1999;Engleberg et al, 2001;Federle et al, 1999;Gryllos et al, 2008;Levin & Wessels, 1998;Trevino et al, 2009). To test whether the transcriptional changes that occur following 4.5S RNA mutation are dependent on a functional covS gene we created a covS/4.5S RNA double mutant strain and compared transcript levels relative to a covS single mutant strain (Fig.…”

“…To investigate the contribution of the 4.5S RNA to the ability of GAS to cause upper respiratory tract infections we used growth and persistence in human saliva as a surrogate for growth and persistence in the upper respiratory tract, as previously described (Shelburne et al, 2005b;Trevino et al, 2009). GAS were inoculated into Fig.…”

Physiological impact of transposable elements encoding DDE transposases in the environmental adaptation of Streptococcus agalactiae

“…Although S. agalactiae is normally a resident of the gastrointestinal tract, it is also able to colonize the throat of human adults. Faecal-oral transmission of S. agalactiae may occur as hand-to-mouth and aerosol contaminations are common for streptococci (Manning et al, 2004;van der Mee-Marquet et al, 2008). It is worth noting that one copy of this ISL3-related transposon (sag1253 to sag1255) is inserted in a putative ICE of strain 2603V/R (ICESa2603), which also contains genes involved in cation and cadmium transport (Davies et al, 2009;Tettelin et al, 2002).…”

“…It was also reported to be a food contaminant. Such ability to survive and develop in numerous different environments indicates a large capability of adaptation (Edwards et al, 2011;Evans et al, 2008;Farley, 2001;Frey et al, 2011;Richards et al, 2011;van der Mee-Marquet et al, 2008.…”

Genome-wide analysis of Streptococcus pyogenes associated with pharyngitis and skin infections. (c2015)

“…In its basic mode of action, the covRS regulon controls streptococcal virulence in response to environmental conditions such as pH, temperature, and ion concentrations (Walker et al, 2014). The covRS regulon controls the expression of around 10 to 15% of the streptococcal genes either directly or indirectly (Trevino et al, 2009). Another feature of the regulon is that it positively modulates the expression of streptococcal pyrogenic exotoxin SpeB, and the hyaluronic acid capsule synthesis, amongst other virulence factors (Sumby et al, 2006).…”