Salmonella manipulates macrophage migration via SteC-mediated myosin light chain activation to penetrate the gut-vascular barrier

The intestinal pathogen Salmonella enterica rapidly enters the bloodstream after the invasion of intestinal epithelial cells, but how Salmonella breaks through the gut-vascular barrier is largely unknown. Here, we report that Salmonella enters the bloodstream through intestinal CX3CR1 + macrophages during early infection. Mechanistically, Salmonella induces the migration/invasion properties of macrophages in a manner dependent on host cell actin and on the pathogen effector SteC. SteC recruits host myosin light chain protein Myl12a and phosphorylates its Ser19 and Thr20 residues. Myl12a phosphorylation results in actin rearrangement, and enhanced migration and invasion of macrophages. SteC is able to utilize a wide range of NTPs other than ATP to phosphorylate Myl12a. We further solved the crystal structure of SteC, which suggests an atypical dimerization-mediated catalytic mechanism. Finally, in vivo data show that SteC-mediated cytoskeleton manipulation is crucial for Salmonella breaching the gut vascular barrier and spreading to target organs. Synopsis Salmonella enters the bloodstream early during infection. Here, the effector protein SteC is found to activate myosin light chain (MLC), thereby facilitating Salmonella dissemination by manipulating macrophage motility. Salmonella enters the bloodstream via infection of intestinal CX3CR1 + macrophages. Salmonella promotes macrophage migration and invasion in an actin- and SteC-dependent manner. SteC acts as an atypical kinase that phosphorylates host MLC using a broad range of NTPs. SteC-mediated MLC activation is essential for Salmonella dissemination within the host. Dissemination of the intestinal pathogen Salmonella enterica within the host depends on motility of infected intestinal macrophages.