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

Mariana I. Capurro, Laura K. Greenfield, Akriti Prashar, Sunny Xia, Majd Abdullah, Harikesh Wong, Xi Zoe Zhong, Nina Bertaux-Skeirik, Jayati Chakrabarti, Iram Siddiqui, Catherine O’Brien, Xianping Dong, Lisa Robinson, Richard M. Peek, Dana J. Philpott, Yana Zavros, Michael Helmrath, Nicola L. Jones

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1411-1423
Number of pages13
JournalNature Microbiology
Volume4
Issue number8
DOIs
StatePublished - Aug 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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