ACTIVATION BY NITRIC-OXIDE OF AN OXIDATIVE-STRESS RESPONSE THAT DEFENDS ESCHERICHIA-COLI AGAINST ACTIVATED MACROPHAGES

Nitric oxide is a free radical (NO.) formed biologically through the o xidation Of L-arginine by nitric oxide synthases. NO. is produced tran siently in mammalian cells for intercellular signaling and in copious quantities to cause cytostasis and cytotoxicity. In the latter situati on, NO. is a deliberate cytotoxic product of activated macrophages, al ong with other reactive oxygen species such as hydrogen peroxide (H2O2 ) and superoxide (O2.-). Escherichia coli has a complex set of respons es to H2O2 and O2.- that involves almost-equal-to 80 inducible protein s; we wondered whether these bacteria might induce analogous defenses against nitric oxide. We show here that a multigene system controlled by the redox-sensitive transcriptional regulator SoxR is activated by NO. in vivo. This induction confers bacterial resistance to activated murine macrophages with kinetics that parallel the production of NO. b y these cells. Elimination of specific SoxR-regulated genes diminishes the resistance of these bacteria to the cytotoxic macrophages. The re quired functions include manganese-containing superoxide dismutase, en donudease IV (a DNA-repair enzyme for oxidative damage), and micF, an antisense regulator of the outer membrane porin OmpF. These results de monstrate that SoxR is a sensor for cellular exposure to NO., and that the soxRS response system may contribute to bacterial virulence.