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

doi:10.1038/s41564-019-0441-6

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 journal › Article › peer-review

93 Citations (Scopus)

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 language	English
Pages (from-to)	1411-1423
Number of pages	13
Journal	Nature Microbiology
Volume	4
Issue number	8
DOIs	https://doi.org/10.1038/s41564-019-0441-6
Publication status	Published - Aug 1 2019

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41564-019-0441-6

Cite this

Capurro, M. I., Greenfield, L. K., Prashar, A., Xia, S., Abdullah, M., Wong, H., Zhong, X. Z., Bertaux-Skeirik, N., Chakrabarti, J., Siddiqui, I., O’Brien, C., Dong, X., Robinson, L., Peek, R. M., Philpott, D. J., Zavros, Y., Helmrath, M., & Jones, N. L. (2019). VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1. Nature Microbiology, 4(8), 1411-1423. https://doi.org/10.1038/s41564-019-0441-6

Capurro, MI, Greenfield, LK, Prashar, A, Xia, S, Abdullah, M, Wong, H, Zhong, XZ, Bertaux-Skeirik, N, Chakrabarti, J, Siddiqui, I, O’Brien, C, Dong, X, Robinson, L, Peek, RM, Philpott, DJ, Zavros, Y, Helmrath, M & Jones, NL 2019, 'VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1', Nature Microbiology, vol. 4, no. 8, pp. 1411-1423. https://doi.org/10.1038/s41564-019-0441-6

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

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.",

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

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AU - Capurro, Mariana I.

AU - Greenfield, Laura K.

AU - Prashar, Akriti

AU - Xia, Sunny

AU - Abdullah, Majd

AU - Wong, Harikesh

AU - Zhong, Xi Zoe

AU - Bertaux-Skeirik, Nina

AU - Chakrabarti, Jayati

AU - Siddiqui, Iram

AU - O’Brien, Catherine

AU - Dong, Xianping

AU - Robinson, Lisa

AU - Peek, Richard M.

AU - Philpott, Dana J.

AU - Zavros, Yana

AU - Helmrath, Michael

AU - Jones, Nicola L.

N1 - 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.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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