Thomas, R.J.; Argent, R.H.; Letley, D.P.; Hardie, K.R.; Atherton, J.C.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA53
Academic Journal
Introduction: H pylori strains possessing the cag Pathogenicity Island (cag Pal) or expressing active vacuolating cytotoxin (vacA) are associated with increased risk of peptic ulceration and gastric adenocarcnoma. Most strains have both or neither of these virulence factors. This is unlikely to be due to genetic linkage as H pylori recombine freely and the loci are distant on the chromosome. We hypothesised that the association was due to a gain of function from possessing both factors. Methods: In two toxigenic cag[sup +] strain backgrounds, 60190 and 84-183, we constructed separate isogenic mutants null for vacA, and for each of two genes encoded on the cag Pal, cagA and cagE. These and wild type strains were passaged in parallel to avoid differential laboratory adaption. For all strains, we assayed vacA activity on cultured epithelial cells by direct counting and by neutral red uptake (NRU) assay; cag-induced pro-inflammatory activity by interleukin-8 (IL-8) ELISA on supernatant from co-cultured epithelial cells; and cagA phosphorylation in epithelial cells by immunoblot with antiphosphotyrosine antibodies. Results (mean±SD) were compared using t tests. Results: cagA[sup -] mutants had increased vacuolating activity compared with cagA[sup +] parent strains, both by direct counting and by NRU assay (60190, 0.085±0.0073 adjusted OD units v 0.131±0.017, p=0.0001). cage mutants had similar effects (60190, 0.085±0.0073 v 0.151±0.018, p=0.00005). As expected, the vacA[sup -] mutants lacked vacuolating activity. In contrast, vacA mutants were similar to vacA[sup +] parent strains in inducing 11.-8 secretion from epithelial cells and n inducing cagA phosphorylation. As expected, the cage mutant but not the cagA mutant had significantly reduced IL-8 stimulating activity (60190, 2145±140.89 pg/ml vs cagE, 662.5±90.85 p=0.O00002) and the cage mutant did not induce cagA phosphorylation in epithelial cells. Similar results...


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