Salmonella utilizes L-arabinose to silence virulence gene expression for accelerated pathogen growth within the host

Carbon source is an important nutrient for bacteria to sustain growth and often acts as a signal that modulates virulence expression. L-arabinose is produced by plants and plays an important role in regulating the global gene expression of bacteria. Previously, we have shown that L-arabinose induces a more severe systemic infection in Salmonella-infected mice with normal microbiota, but does not affect the disease progression in mice with microbiota depleted by antibiotic treatment. The underlying mechanism remains elusive. In this study, we demonstrate that L-arabinose represses the expression of Salmonella type III secretion system 1 (T3SS-1) genes by negatively regulating the activity of the cyclic 3' 5'-AMP (cAMP)-cAMP receptor protein (CRP) complex. The cAMP-CRP complex can activate ribosome-associated inhibitor A, encoded by yfiA, to maintain the stability of HilD, a key transcriptional regulator of T3SS-1. L-arabinose supplementation promotes Salmonella initial bloom in the antibiotic-pretreated mouse gut and ultimately compensates for reduced virulence within the host. These results decipher the molecular mechanism by which cAMP-CRP directs regulatory changes of virulence in response to L-arabinose in Salmonella. It further implies that Salmonella exploits L-arabinose both as a nutrient and a regulatory signal to maintain a balance between growth and virulence within the host.