Fig 7. A schematic model of virulence regulation by C3564/C3565 (OrhK/OrhR).

We propose that once inside host macrophages, UPEC is able to sense the presence of ROS through the histidine kinase (HK) C3564, which, in turn, transphosphorylates the response regulator (RR) C3565; phosphorylated C3565 is an active form and therefore binds to the promoter region of c3566 and upregulates c3566-c3568-hlyCABD expression. Upon acylation by HlyC, hemolysin encoded by hlyA becomes activated, which is translocated by type I secretion machinery containing HlyB and HlyD. C3566 is thought to be membrane-bound, while C3567 and C3568 are periplasmic, and the Msr system C3566-C3567 functions to repair proteins by converting MetSO to Met, thus providing protection. Meanwhile, increased hemolysin production triggers pro-caspase-1 and GSDMD processing, and the resultant GSDMD-N polymerizes and forms pores on the host cell membrane, eventually causing host cell pyroptosis. The question mark (?) indicates a pathway yet to be discovered.