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Infection and Immunity, December 2006, p. 6599-6614, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01085-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Helicobacter pylori VacA Toxin Promotes Bacterial Intracellular Survival in Gastric Epithelial Cells{triangledown} ,{dagger}

M. R. Terebiznik,1,3 C. L. Vazquez,2 K. Torbicki,1,3 D. Banks,1,3 T. Wang,4 W. Hong,4 S. R. Blanke,5 M. I. Colombo,2 and N. L. Jones1,3*

Infection, Injury, Immunity and Repair Program, Hospital for Sick Children, Toronto, Ontario, Canada,1 IHEM-CONICET, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo, Mendoza, Argentina,2 Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada,3 Laboratory of Membrane Biology, Institute of Molecular and Cell Biology, Proteos, Singapore, Republic of Singapore,4 Department of Microbiology and Institute for Genomic Biology, University of Illinois, Urbana, Illinois5

Received 11 July 2006/ Returned for modification 18 August 2006/ Accepted 19 September 2006

Helicobacter pylori colonizes the gastric epithelium of at least 50% of the world's human population, playing a causative role in the development of chronic gastritis, peptic ulcers, and gastric adenocarcinoma. Current evidence indicates that H. pylori can invade epithelial cells in the gastric mucosa. However, relatively little is known about the biology of H. pylori invasion and survival in host cells. Here, we analyze both the nature of and the mechanisms responsible for the formation of H. pylori's intracellular niche. We show that in AGS cells infected with H. pylori, bacterium-containing vacuoles originate through the fusion of late endocytic organelles. This process is mediated by the VacA-dependent retention of the small GTPase Rab7. In addition, functional interactions between Rab7 and its downstream effector, Rab-interacting lysosomal protein (RILP), are necessary for the formation of the bacterial compartment since expression of mutant forms of RILP or Rab7 that fail to bind each other impaired the formation of this unique bacterial niche. Moreover, the VacA-mediated sequestration of active Rab7 disrupts the full maturation of vacuoles as assessed by the lack of both colocalization with cathepsin D and degradation of internalized cargo in the H. pylori-containing vacuole. Based on these findings, we propose that the VacA-dependent isolation of the H. pylori-containing vacuole from bactericidal components of the lysosomal pathway promotes bacterial survival and contributes to the persistence of infection.

* Corresponding author. Mailing address: Hospital for Sick Children, 555 University Ave., Toronto, Canada M5G 1X9. Phone: 416-813 7062. Fax: 416-813 6531. E-mail: nicola.jones{at}sickkids.ca.

{triangledown} Published ahead of print on 25 September 2006.

Editor: D. L. Burns

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Infection and Immunity, December 2006, p. 6599-6614, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01085-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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