Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: A strategy for bacterial survival

The antimicrobial effect of nitric oxide (NO) is an essential part of innat e immunity. The vigorous host response to the human gastric pathogen Helico bacter pylori fails to eradicate the organism, despite up-regulation of ind ucible No synthase (iNOS) in the gastric mucosa. Here we report that wild-t ype strains of H. pylori inhibit NO production by activated macrophages at physiologic concentrations of L-arginine, the common substrate for iNOS and arginase. Inactivation of the gene rocF, encoding constitutively expressed arginase in H. pylori, restored high-output NO production by macrophages. By using HPLC analysis, we show that L-arginine is effectively consumed in the culture medium by wild-type but not arginase-deficient H. pylori. The s ubstantially higher levels of NO generated by macrophages cocultured with r ocF-deficient H. pylori resulted in efficient killing of the bacteria, wher eas wild-type H. pylori exhibited no loss of survival under these condition s. Killing of the arginase-deficient H. pylori was NO-dependent, because pe ritoneal macrophages from iNOS(-/-) mice failed to affect the survival of t he rocF mutant. Thus, bacterial arginase allows H. pylori to evade the immu ne response by down-regulating eukaryotic NO production.