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J. Biol. Chem., Vol. 278, Issue 29, 26734-26741, July 18, 2003

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Determinants of Non-toxicity in the Gastric Pathogen Helicobacter pylori^*

Darren P. Letley , Joanne L. Rhead, Rachel J. Twells, Brian Dove and John C. Atherton 

From the Division of Gastroenterology and Institute of Infections, Immunity and Inflammation, University of Nottingham, C Floor, West Block, Queen's Medical Centre, Clifton Boulevard, Nottingham NG7 2UH, United Kingdom

The Helicobacter pylori vacuolating cytotoxin gene, vacA, is naturally polymorphic, the two most diverse regions being the signal region (which can be type s1 or s2) and the mid region (m1 or m2). Previous work has shown which features of vacA make peptic ulcer and gastric cancer-associated type s1/m1 and s1/m2 strains toxic. vacA s2/m2 strains are associated with lower peptic ulcer and gastric cancer risk and are non-toxic. We now define the features of vacA that determine the non-toxicity of these strains. To do this, we deleted parts of vacA and constructed isogenic hybrid strains in which regions of vacA were exchanged between toxigenic and non-toxigenic strains. We showed that a naturally occurring 12-amino acid hydrophilic N-terminal extension found on s2 VacA blocks vacuolating activity as its removal (to make the strain s1-like) confers activity. The mid region of s2/m2 vacA does not cause the non-vacuolating phenotype, but if VacA is unblocked, it confers cell line specificity of vacuolation as in natural s1/m2 strains. Chromosomal replacement of vacA in a non-toxigenic strain with vacA from a toxigenic strain confers full vacuolating activity proving that this activity is entirely controlled by elements within vacA. This work defines why H. pylori strains with different vacA allelic structures have differing toxicity and provides a rational basis for vacA typing schemes.

Received for publication, April 17, 2003

^* This work was supported in part by a grant from the Medical Research Council (MRC) (United Kingdom). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an MRC Senior Clinical Fellowship.

To whom correspondence should be addressed. Tel.: 44-0-115-970-9063; Fax: 44-0-115-970-9923; E-mail: darren.letley{at}nottingham.ac.uk.

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