Overview of the regulatory networks in expression of group A streptococcal virulence genes. +, positive regulation; —, negative regulation. Overview of the regulatory networks in expression of group A streptococcal virulence genes. +, positive regulation; —, negative regulation. Short dashed lines indicate CovR regulation, and long dashed lines represent regulation by Mga. Solid lines show the correlation between growth phase (exponential [light lines] or stationary [darker lines]). As shown in the figure, Mga activates transcription of several genes, including those for M protein (emm), C5a peptidase (scpA), M-like proteins (mrp, enn, and fcR), serum opacity factor (sof), and secreted inhibitor of complement (sic) (95, 101, 355, 358, 422). Mga feeds back to positively regulate itself and functions as a 62-kDa protein to bind to the promotor region of genes that it regulates (417). The genes involved in the mga regulon are shown in Table 3, and an overview of regulation is shown in the diagram above. A global negative regulator of mga was identified in a few strains and called nra. In addition to repressing Mga synthesis 4- to 16-fold, nra was a negative regulator ofprtF2, the gene for the fibronectin-binding protein F2, and the collagen-binding protein gene (cpa) in group A streptococci. The Nra protein sequence was 62% homologous to RofA, a positive transcriptional regulator of the fibronectin-binding protein (prtF) and itself in response to increased oxygen levels (426). RofA and Mga may influence the expression of genes involved in adhesion in different environments (426).csrR and csrS or covR andcovS are a pair of genetic loci in group A streptococci that encode a two-component regulatory system (327). Inactivation of csrR or covR resulted in a striking increase in transcription of the capsule synthesis genes of the hasoperon and a corresponding increase in hyaluronic acid capsule production (327). Subsequent work confirmed these observations and demonstrated binding of the CsrR protein to the promoter region upstream of the has operon (42). The CsrR or CovR protein acts as a transcriptional regulator. Production of a nonpolar mutation in csrR or covRincreased transcription of several other virulence genes, includingska (streptokinase), sagA (streptolysin O), andspeF (mitogenic factor) but had no effect on mga,emm, scpA, speB, or speC. Thus, the CovR or CsrR response regulator repressed transcription of several virulence operons in group A streptococci (172). Since multiple unrelated genes were controlled by csrR, an alternative nomenclature was given to the csrR-csrS locus,covR-covS for control of virulence genes. ThecsrR-csrS or covR-covS sensor-regulator gene pair represent a new regulatory pathway affecting expression of several group A streptococcal virulence genes which are not regulated bymga and has been found in all group A streptococcal strains tested (172). (Reprinted from reference172 with permission from the publisher.)‏ Madeleine W. Cunningham Clin. Microbiol. Rev. 2000; doi:10.1128/CMR.13.3.470