Diversity of Helicobacter pylori vacA and cagA Genes and Relationship to VacA and CagA Protein Expression, Cytotoxin Production, and Associated Diseases

Abstract

The vacuolating cytotoxin and the cytotoxin-associated protein, encoded by vacA and cagA, respectively, are important virulence determinants of Helicobacter pylori. Sixty-five H. pylori strains were isolated from dyspeptic patients (19 with peptic ulcer disease, 43 with chronic gastritis, and 3 with gastric cancer) and studied for differences in thevacA and cagA genes and their relationship to VacA and CagA expression, cytotoxin activity, and the clinical outcome of infection. By PCR, fifty-four (83.1%) of 65 strains had thevacA signal sequence genotype s1 and only 10 (15.4%) had the type s2. After primer modification, the vacAmiddle-region types m1 and m2 were detected in 24 (36.9%) and 41 (63.1%) strains, respectively. The combinations s1-m2 (31 [47.7%]) and s1-m1 (23 [35.4%]) occurred more frequently than s2-m2 (10 [15.4%]) (P = 0.01). No strain with the combination s2-m1 was found. All 19 patients with peptic ulcers harbored type s1 strains, in contrast to 32 (74.4%) of 43 patients with gastritis (P = 0.02). The vacA genotype s1 was associated with the presence of cagA (P < 0.0001), VacA expression (P < 0.0001), and cytotoxin activity (P = 0.003). The cagA gene was detectable in 48 (73.8%) of 65 isolates and present in 16 (84.2%) of 19 ulcer patients and 29 (67.4%) of 43 patients with gastritis (P = 0.17). The vacA genotypes of GermanH. pylori isolates are identical to those previously reported. H. pylori strains of vacA type s1 are associated with the occurrence of peptic ulceration and the presence ofcagA, cytotoxin activity, and VacA expression.

Test of the hypothesis that vacA genotypes of helicobacter pylori correlate with CagA status, cytotoxin production, or clinical outcome

“…Other recent data are consistent with our finding that vacA genotyping appears to offer little in the way of discrimination with regard to clinical presentation. A MEDLINE search of the English language literature, starting with Atherton's first vacA publication in July 1995 and continuing to July 1998, as well as the present study, identify a number of studies reporting vacA genotyping in patients with peptic ulcer or nonulcer dyspepsia from a number of different countries, including 12 studies from Europe (Portugal, The Netherlands, UK, Germany, France, Sweden) or the United States and 4 from Asia (Japan, China, Taiwan) [7,8,20,[23][24][25][26][27][28][29][30][31][32][33][34]. Overall, the available data concern more than 1500 patients (Table 7).…”

Helicobacter pylorivacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity

“…Several recent reports have indicated the capacity of VacA to induce apoptosis of gastric epithelial cells both in vitro and in vivo (Rudi et al ., 1998a;Peek et al ., 1999;Kuck et al ., 2001). Apoptosis within the gastric mucosa is strongly associated with the presence of H. pylori (Mannick et al ., 1996;Moss et al ., 1996;Jones et al ., 1997;Rudi et al ., 1998b), and H. pylori has been shown to induce apoptosis in murine and gerbil models of infection (Wang et al ., 1998;Houghton et al ., 2000;Peek et al ., 2000;Israel et al ., 2001;Jones et al ., 2002).…”

Reduced intracellular survival of Helicobacter pylori vacA mutants in comparison with their wild-types indicates the role of VacA in pathogenesis

“…The vacuolating cytotoxin (VacA) is probably involved in H. pylori pathogenesis since strains from peptic ulcer patients to a larger degree will produce VacA [16,17]. Although the H. pylori cytotoxin has been linked to duodenal and gastric ulcers, the precise role of vacA in H. pylori-related disease pathogenesis is unknown.…”