THE AI-3/EPINEPHRINE/NOREPINEPHRINE INTER-KINGDOM SIGNALING SYSTEM IS IMPORTANT FOR SALMONELLA ENTERICA SEROVAR TYPHIMURIUM PATHOGENICITY IN VIVO.

Cristiano Gallina Moreira (UTSWMED); Vanessa Sperandio (UTSWMED)

Inter-kingdom chemical signaling between bacteria and their mammalian hosts can be achieved through the host stress hormones epinephrine (Epi) and/or norepinephrine (NE), and the bacterial signal autoinducer-3 (AI-3). The QseC sensor kinase is an adrenergic bacterial receptor that responds to these three signals by increasing its autophosphorylation and initiating a complex phosphoreley cascade involved in regulation of virulence traits. The QseC regulon has been extensively documented to be important for the regulation of flagella and motility, and virulence genes in enterohemorrhagic E. coli (EHEC). QseC is found in several bacteria, including Salmonella sp. Salmonella enterica serovar Typhimurium. QseC in Salmonella enterica serovar Typhimurium was recently implicated in swine colonization and norepinephrine-enhanced motility. Here we show that QseC plays an important role in Salmonella enterica serovar Typhimurium pathogenicity in vivo. We have generated a qseC mutant in strain SL1344. The qseC mutant was attenuated for survival within J774 macrophages and invasion of epithelial HeLa cells. Invasion was restored to WT levels upon complementation. Survival within J774 macrophages was inhibited by both alpha and beta adrenergic antagonists. The qseC mutant was also attenuated for systemic infection in 129x1/SvJ mice. Transcription of sopB, invF and sifA was decreased in the qseC mutant compared to expression in WT in vitro and in vivo in the spleens and livers of mice. Additionally, transgenic mice that do not express DBH (dopamine beta hydroxylase), i.e. unable to produce epinephrine/norepinephrine, had a different susceptibility to Salmonella infection compared to DBH heterozygous and wild-type mice. These data suggest that inter-kingdom signaling in Salmonella enterica serovar Typhimurium plays an important role in pathogenesis in vivo, and that the QseC sensor kinase regulates expression of virulence genes in Salmonella. A better understanding of the QseBC system, in addition to other two-component systems, will contribute to a better understanding of Salmonella pathogenesis.