SUMMARY Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes.

No abstract

The antimicrobial effect of nitric oxide (NO) is an essential part of innate immunity. The vigorous host response to the human gastric pathogen Helicobacter pylori fails to eradicate the organism, despite up-regulation of inducible NO synthase (iNOS) in the gastric mucosa. Here we report that wild-type 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 substantially higher levels of NO generated by macrophages cocultured with rocF-deficient H. pylori resulted in efficient killing of the bacteria, whereas wild-type H. pylori exhibited no loss of survival under these conditions. Killing of the arginase-deficient H. pylori was NO-dependent, because peritoneal macrophages from iNOS ؊/؊ mice failed to affect the survival of the rocF mutant. Thus, bacterial arginase allows H. pylori to evade the immune response by down-regulating eukaryotic NO production. Helicobacter pylori is a Gram-negative microaerophilic bacterium, which selectively colonizes the human stomach. Current prevalence of H. pylori is Ϸ40% of the population in the U.S. (1) and substantially higher in underdeveloped regions. H. pylori causes chronic gastritis, peptic ulcers, and gastric carcinoma and lymphoma, leading to its classification as a Class I carcinogen (2). Despite inciting substantial acute and chronic immune and inflammatory responses, H. pylori infection generally persists for the life of the host. Understanding how the bacterium evades the host response remains a critical issue in managing the public health burden of this infection.Nitric oxide (NO) is a central component of innate immunity and an effective antimicrobial agent (3). This activity is especially marked for intracellular pathogens such as Mycobacterium tuberculosis (4) and Leishmania major (5), which are killed by an NO-dependent mechanism. Reactive nitrogen intermediates can also effectively kill extracellular parasites (6, 7) and bacteria such as Escherichia coli (8). Chemical sources of NO and peroxynitrite have a direct toxic effect on H. pylori (9, 10). However, the effect of cell-derived NO on H. pylori has not been investigated. The survival of H. pylori, despite marked induction of inducible NO synthase (iNOS) in macrophages (11) and gastric tissues (12), suggests that the bacterium has developed mechanisms to avoid NO-dependent killing.Arginases are a primordial enzyme family, which are highly conserved across kingdoms (13). Mammalian arginases compete with NO synthases for the common substrate L-arginine (14), hydrolyzing the amino acid to urea and L-ornithine. Therefore, arginases can regulate cellular NO production (15, 16) and counteract the biological effects of NO (7,17). H....

No abstract