2. Academic Validation
  3. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1

VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1

  • Nat Microbiol. 2019 Aug;4(8):1411-1423. doi: 10.1038/s41564-019-0441-6.
Mariana I Capurro 1,  Laura K Greenfield 1,  Akriti Prashar 1,  Sunny Xia 1,  Majd Abdullah 1,  Harikesh Wong 2,  Xi Zoe Zhong 3,  Nina Bertaux-Skeirik 4,  Jayati Chakrabarti 4,  Iram Siddiqui 5,  Catherine O'Brien 6,  Xianping Dong 3,  Lisa Robinson 2,  Richard M Peek Jr 7,  Dana J Philpott 8,  Yana Zavros 4,  Michael Helmrath 9,  Nicola L Jones 10
Affiliations

Affiliations

  • 1 Department of Paediatrics and Physiology, University of Toronto; Division of Gastroenterology, Hepatology and Nutrition, and Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 2 Department of Paediatrics, University of Toronto; Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 4 Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA.
  • 5 Department of Pathology, University of Toronto; The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 6 University Health Network, University of Toronto, Toronto, Ontario, Canada.
  • 7 Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 8 Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • 9 Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 10 Department of Paediatrics and Physiology, University of Toronto; Division of Gastroenterology, Hepatology and Nutrition, and Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
PMID: 31110360 DOI: 10.1038/s41564-019-0441-6
Abstract

Helicobacter pylori Infection is a proven carcinogen for gastric Cancer. Its virulence factor vacuolating cytotoxin A (VacA) promotes more severe disease and gastric colonization. VacA, by an unknown mechanism, usurps lysosomal and Autophagy pathways to generate a protected reservoir for H. pylori that confers Bacterial survival in vitro. Here, we show the existence of a VacA-generated intracellular niche in vivo that protects the bacteria from Antibiotic treatment and leads to Infection recrudescence after therapy. Furthermore, we report that VacA targets the lysosomal Calcium Channel TRPML1 to disrupt endolysosomal trafficking and mediate these effects. Remarkably, H. pylori that lack toxigenic VacA colonize enlarged dysfunctional lysosomes in the gastric epithelium of trpml1-null mice, where they are protected from eradication therapy. Furthermore, a small molecule agonist directed against TRPML1 reversed the toxic effects of VacA on endolysosomal trafficking, culminating in the clearance of intracellular bacteria. These results suggest that TRPML1 may represent a therapeutic target for chronic H. pylori Infection.

Figures