MOSAICISM IN VACUOLATING CYTOTOXIN ALLELES OF HELICOBACTER-PYLORI - ASSOCIATION OF SPECIFIC VACA TYPES WITH CYTOTOXIN PRODUCTION AND PEPTIC-ULCERATION

Approximately 50% of Helicobacter pylori strains produce a cytotoxin, encoded by vacA, that induces vacuolation of eukaryotic cells. Analysi s of a clinically isolated tox(-) strain (Tx30a) indicated secretion o f a 93-kDa product from a 3933 base pair vacA open reading frame. Char acterization of 59 different H. pylori isolates indicated the existenc e of three different families of vacA signal sequences (s1a, s1b, and s2) and two different families of middle-region alleles (m1 and m2). A ll possible combinations of these vacA regions were identified, with t he exception of s2/m1 (p < 0.001); this mosaic organization implies th at recombination has occurred in vivo between vacA alleles. Type s1/m1 strains produced a higher level of cytotoxin activity in vitro than t ype s1/m2 strains; none of 19 type s2/m2 strains produced detectable c ytotoxin activity. The presence of cagA (cytotoxin-associated gene A) was closely associated with the presence of vacA signal sequence type s1 (p < 0.001). Among patients with past or present peptic ulceration, 21 (91%) of 23 harbored type s1 strains compared with 16 (48%) of 33 patients without peptic ulcers; only 2 (10%) of 19 subjects harboring type s2 strains had past or present peptic ulcers (p < 0.005). Thus, s pecific vacA genotypes of H. pylori strains are associated with the le vel of in vitro cytotoxin activity as well as clinical consequences.