Comparison of control of Listeria by nitric oxide redox chemistry from murine macrophages and no donors: Insights into listeriocidal activity of oxidative and nitrosative stress

The physiological function of nitric oxide (NO) in the defense against path ogens is multifaceted. The exact chemistry by which NO combats intracellula r pathogens such as Listeria monocytogenes is yet unresolved. We examined t he effects of NO exposure, either delivered by NO donors ol generated in si tu within ANA-1 murine macrophages. on L. monocytogenes growth. Production of NO by the two NONOate compounds PAPA/NO (NH2(C3H6)(N[N(O)NO]C3H7)) and D EA/NO (Na(C2H5)(2)N[N(O)NO]) resulted in L. monocytogenes cytostasis with m inimal cytotoxicity. Reactive oxygen species generated from xanthine oxidas e/hypoxanthine were neither bactericidal nor cytostatic and did not alter t he action of NO. L. monocytogenes growth was also suppressed upon internali zation into ANA-1 murine macrophages primed with interferon-gamma (INF-gamm a) + tumor necrosis factor-alpha TNF-alpha or INF-gamma + lipid polysacchar ide (LPS). Growth suppression correlated with nitrite formation and nitrosa tion of 2,3-diaminonaphthalene elicited by stimulated murine macrophages. T his: nitrosative chemistry was not dependent upon nor mediated by interacti on with reactive oxygen species (ROS), but resulted solely from NO and inte rmediates related to nitrosative stress. The role of nitrosation in control ling L. monocytogenes was further examined by monitoring the effects of exp osure to NO on an important virulence factor, Listeriolysin O, which was in hibited under nitrosative conditions. These results suggest that nitrosativ e stress mediated by macrophages is an important component of the immunolog ical arsenal in controlling L. monocytogenes infections. (C) 2001 Elsevier Science Inc.