Co-regulation of CodY and (p)ppGpp synthetases on morphology and pathogenesis of Streptococcus suis

CodY and (p)ppGpp synthetases are two important global regulators of bacteria. In some pathogens, such as Listeria monocytogenes, the GTP pool links these two regulatory systems, and introducing a codY mutant into the ΔrelA strain restored the pathogenicity of the attenuated ΔrelA mutant. In previous studies, we identified the (p)ppGpp synthetases (RelA and RelQ) and CodY of Streptococcus suis. To understand the interrelationships between these two regulators in S. suis, a ΔrelAΔrelQΔcodY mutant was constructed, and its growth, morphology, and pathogenicity were evaluated. Compared with ΔrelAΔrelQ, ΔcodY, its growth was very slow, but its chain length was partly restored to the wild-type length and its capsule became thick and rough. The adherence, invasion ability, and resistance to whole-blood killing in vitro of ΔrelAΔrelQΔcodY and its lethality and colonization ability in mice were clearly reduced, which differs from the effects of these mutations in L. monocytogenes. An analysis of gene expression showed that CodY interacted with the relA promoter in a GTP-independent manner to positively regulate the expression of relA. The introduction of a codY mutant into the ΔrelAΔrelQ strain further reduced the expression of virulence factors, which suggests a novel interaction between the (p)ppGpp synthetases and CodY. This study extends our understanding of the relationship between the (p)ppGpp-mediated stringent response and the regulation of CodY in S. suis.