Working models of the regulatory networks of c-di-GMP signaling in S. typhimurium leading to suppression of invasion and IL-8 induction.

(A) A model of the c-di-GMP signaling network for the suppression of the invasion phenotype by c-di-GMP signaling. Shown are di-guanylate cyclases and phosphodiesterases with the most pronounced effect on invasion. Activity of the di-guanylate cyclases STM1987 and STM4551 and the phosphodiesterases STM3611 and STM4262 create different c-di-GMP pools which subsequently affect target outputs. Upon elevated c-di-GMP, the invasion phenotype is negatively regulated by c-di-GMP signaling through the cellulose synthase BcsA and the biofilm regulator CsgD. CsgD inhibits secretion of TTSS-1 effector protein SipA. SipA secretion is affected by GGDEF and EAL domain proteins. Whether motility affects the invasion phenotype needs to be demonstrated. (B) Model of the c-di-GMP signaling network for the suppression of the IL-8 induction phenotype by c-di-GMP signaling. The c-di-GMP pool created by the di-guanylate cyclase STM1283 is degraded by the phosphodiesterases STM0468, STM1703, STM2503, STM3375 and STM4264 which are shown in the order of affection of the IL-8 induction phenotype. Upon elevation of c-di-GMP the resulting c-di-GMP pool is suggested to stimulate CsgD expression which subsequently represses IL-8 induction.