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

Résultat de recherche: Articleexamen par les pairs

93 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)1411-1423
Nombre de pages13
JournalNature Microbiology
Volume4
Numéro de publication8
DOI
Statut de publicationPublished - août 1 2019

Note bibliographique

Funding Information:
We thank S. Slaugenhaupt for the Trpml1-deficient mice, S. Blanke for the purified VacA toxin and anti-VacA polyclonal antibody and J. Atherton for the H. pylori SS1 strains. This work was supported by the Canadian Institutes of Health Research (CIHR), the Canadian Association of Gastroenterology (CAG) and the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition Foundation. L.K.G. was supported by a CIHR/CAG/Canadian Crohn’s and Colitis and CIHR/CAG/AbbVie Pharmaceuticals Canada Fellowship.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus Subject Areas

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

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