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J. Biol. Chem., Vol. 278, Issue 35, 32602-32607, August 29, 2003

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Regulation of Dinucleoside Polyphosphate Pools by the YgdP and ApaH Hydrolases Is Essential for the Ability of Salmonella enterica serovar Typhimurium to Invade Cultured Mammalian Cells^*

Thamir M. Ismail , C. Anthony Hart  and Alexander G. McLennan  ¶

From the School of Biological Sciences and Department of Medical Microbiology and Genito-urinary Medicine, University of Liverpool, Liverpool L69 7ZB, United Kingdom

The ygdP and apaH genes of Salmonella enterica serovar Typhimurium (S. Typhimurium) encode two unrelated dinucleoside polyphosphate (Np_nN) hydrolases. For example, YgdP cleaves diadenosine tetraphosphate (Ap₄A) producing AMP and ATP, while ApaH cleaves Ap₄A producing 2ADP. Disruption of ygdP, apaH individually, and disruption of both genes together reduced intracellular invasion of human HEp-2 epithelial cells by S. Typhimurium by 9-, 250-, and 3000-fold, respectively. Adhesion of the mutants was also greatly reduced compared with the wild type. Invasive capacity of both single mutants was restored by transcomplementation with the ygdP gene, suggesting that loss of invasion was due to increased intracellular Np_nN. The normal level of 3 µM adenylated Np_nN (Ap_nN) was increased 1.5-, 3.5-, and 10-fold in the ygdP, apaH and double mutants, respectively. Expression of the putative ptsP virulence gene downstream of ygdP was not affected in the ygdP mutant. Analysis of 19 metabolic enzyme activities and the ability to use a range of carbohydrate carbon sources revealed a number of differences between the mutants and wild type. The increase in intracellular Np_nN in the mutants appears to cause changes in gene expression that limit the ability of S. Typhimurium to adhere to and invade mammalian cells.

Received for publication, June 6, 2003 , and in revised form, June 23, 2003.

^* This work was supported by Wellcome Trust Project Grant 058468 (to A. G. M. and C. A. H.). 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.

^¶ To whom correspondence should be addressed: School of Biological Sciences, Biosciences Bldg., University of Liverpool, P. O. Box 147, Liverpool L69 7ZB, UK. Tel.: 44-151-795-4426; Fax: 44-151-795-4404; E-mail: agmclen{at}liv.ac.uk.

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