Association between polymorphisms in the csrRS two-component regulatory system and invasive group A streptococcal infection.

The csrRS two-component regulatory system is an important element in the pathogenesis of group A Streptococcus (GAS). The main goal of this study is to understand the association between csrRS polymorphisms and GAS infection. We sequenced the csrRS genes from 172 clinical isolates, including 81 invasive and 91 noninvasive isolates, and then employed phylogenetic analyses to determine the consequences of the csrRS polymorphisms. In total, 13 and 26 polymorphic loci were detected in the csrR and csrS genes, respectively. These polymorphisms constituted 14 csrR and 25 csrS alleles, producing two CsrR and seven CsrS variants, respectively. Three invasive isolates contained an indel in csrS, but no indel was identified in csrR. The frequency and distribution of polymorphisms in csrR and csrS was significantly different between the invasive and noninvasive infection isolates (p < 0.001). For CsrR, only one noninvasive isolate was identified to have a V29I mutation. The amino acid substitutions in CsrS included S32P (0.6 %), E265G (0.6 %), E265K (0.6 %), I332V (1.7 %), and N498K (82.6 %). Isolates with an N498K single mutation were more likely to be associated with invasive infections (p < 0.001). The dN/dS ratio indicated that both csrR and csrS were under purifying selection. The fixation index suggested a moderate evolutionary differentiation of the csrR and csrS alleles between invasive and noninvasive isolates. The identification of these genetic differences within the csrRS loci will provide a better understanding of the pathogenesis of GAS.