A bacterial “shield and sword”: A previously uncharacterized two-component system protects uropathogenicEscherichia colifrom host-derived oxidative insults and promotes hemolysin-mediated host cell pyroptosis

Uropathogenic Escherichia coli (UPEC) deploys an array of virulence factors to successfully establish urinary tract infections. Coordinated expression of these various virulence factors is critical for UPEC’s overall fitness in the host. Two-component signaling systems (TCSs) are a major mechanism by which bacteria sense environmental cues and initiate adaptive responses. Here, we report a previously uncharacterized TCS encoded on a pathogenicity island in UPEC that directly activates the expression of a putative methionine sulfoxide reductase system (C3566/C3567) and a pore-forming α-hemolysin in response to host-derived hydrogen peroxide (H 2 O 2 ) exposure. The TCS increases UPEC resistance to H 2 O 2 in vitro and survival in macrophages in tissue culture via C3566/C3567. Additionally, the TCS mediates α-hemolysin-induced renal epithelial cell and macrophage death via a pyroptosis pathway. Taken together, our data suggest a paradigm in which this signal transduction system coordinates both bacterial pathogen defensive and offensive traits in the presence of host-derived signals.