Molecular basis of the hepatobiliary tropism of typhoid toxin promoting <i>Salmonella</i> pathogenicity.

Abstract

<i>Salmonella</i> Typhi assembles and secretes two forms of typhoid toxin by using two receptor-binding subunits, PltB and PltC. Unlike PltB typhoid toxin, little is known about the tropism and functional consequences of PltC typhoid toxin. Here, we report that PltC typhoid toxin has hepatobiliary tropism through the binding of PltC subunit to sulfated glycans on liver sinusoidal endothelial cells and gallbladder epithelial cells. Critical bacterial and mammalian cell factors involved are PltC R109 residue and carbohydrate sulfotransferases CHST2/4. One notable effect associated with the hepatobiliary tropism of PltC typhoid toxin is a reduction in bile acids, consequently promoting <i>S.</i> Typhi pathogenicity in infected mice. Similarly, bile acids serve as anti-<i>S.</i> Typhi infectivity agents at the cellular level, as bile acids inhibit invasion of mammalian cells. These findings highlight a distinct mechanism used by a bacterial exotoxin promoting the pathogenicity of the cognate bacteria and offer insights into the development of antivirulence agents against PltC typhoid toxin and/or <i>S.</i> Typhi.