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

被引：89

作者：

Capurro, Mariana, I ^{[1
,2
,3
]}

Greenfield, Laura K. ^{[1
,2
,3
]}

Prashar, Akriti ^{[1
,2
,3
]}

Xia, Sunny ^{[1
,2
,3
]}

Abdullah, Majd ^{[1
,2
,3
]}

Wong, Harikesh ^{[3
,4
]}

Zhong, Xi Zoe ^{[5
]}

Bertaux-Skeirik, Nina ^{[6
]}

Chakrabarti, Jayati ^{[6
]}

Siddiquis, Ram ^{[7
,8
]}

O'Brien, Catherine ^{[9
]}

Dong, Xianping ^{[5
]}

Robinson, Lisa ^{[3
,4
]}

Peek, Richard M., Jr. ^{[10
]}

Philpott, Dana J. ^{[11
]}

Zavros, Yana ^{[6
]}

Helmrath, Michael ^{[12
]}

Jones, Nicola L. ^{[1
,2
,3
]}

机构：

[1] Univ Toronto, Dept Paediat & Physiol, Toronto, ON, Canada

[2] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[3] Hosp Sick Children, Cell Biol Program, Toronto, ON, Canada

[4] Univ Toronto, Dept Paediat, Toronto, ON, Canada

[5] Dalhousie Univ, Dept Physiol & Biophys, Halifax, NS, Canada

[6] Univ Cincinnati, Dept Mol & Cellular Physiol, Cincinnati, OH USA

[7] Univ Toronto, Dept Pathol, Toronto, ON, Canada

[8] Hosp Sick Children, Toronto, ON, Canada

[9] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada

[10] Vanderbilt Univ, Div Gastroenterol, Med Ctr, Nashville, TN USA

[11] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[12] Cincinnati Childrens Hosp Med Ctr, Div Pediat Gen & Thorac Surg, Cincinnati, OH 45229 USA

来源：

NATURE MICROBIOLOGY | 2019年 / 4卷 / 08期

基金：

加拿大健康研究院;

关键词：

VACUOLATING CYTOTOXIN; MOUSE MODEL; CATHEPSIN-D; INFECTION; AUTOPHAGY; COLONIZATION; CHLORIDE; PATHWAY;

D O I：

10.1038/s41564-019-0441-6

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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.

引用

页码：1411 / 1423

页数：13

共 46 条

[1] Role of TRP Channels in the Regulation of the Endosomal Pathway [J].

Abe, Ken ;

Puertollano, Rosa .

PHYSIOLOGY, 2011, 26 (01) :14-22

[2] CD44 Plays a Functional Role in Helicobacter pylori-induced Epithelial Cell Proliferation [J].

Bertaux-Skeirik, Nina ;

Feng, Rui ;

Schumacher, Michael A. ;

Li, Jing ;

Mahe, Maxime M. ;

Engevik, Amy C. ;

Javier, Jose E. ;

Peek, Richard M., Jr. ;

Ottemann, Karen ;

Orian-Rousseau, Veronique ;

Boivin, Gregory P. ;

Helmrath, Michael A. ;

Zavros, Yana .

PLOS PATHOGENS, 2015, 11 (02)

[3] Sortilin mediates the lysosomal targeting of cathepsins D and H [J].

Canuel, Maryssa ;

Korkidakis, Ann ;

Konnyu, Kristin ;

Morales, Carlos R. .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 373 (02) :292-297

[4] Genomic mapping of phosphorothioates reveals partial modification of short consensus sequences [J].

Cao, Bo ;

Chen, Chao ;

DeMott, Michael S. ;

Cheng, Qiuxiang ;

Clark, Tyson A. ;

Xiong, Xiaolin ;

Zheng, Xiaoqing ;

Butty, Vincent ;

Levine, Stuart S. ;

Yuan, George ;

Boitano, Matthew ;

Khai Luong ;

Song, Yi ;

Zhou, Xiufen ;

Deng, Zixin ;

Turner, Stephen W. ;

Korlach, Jonas ;

You, Delin ;

Wang, Lianrong ;

Chen, Shi ;

Dedon, Peter C. .

NATURE COMMUNICATIONS, 2014, 5

[5] BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release [J].

Cao, Qi ;

Zhong, Xi Zoe ;

Zou, Yuanjie ;

Zhang, Zhu ;

Toro, Ligia ;

Dong, Xian-Ping .

DEVELOPMENTAL CELL, 2015, 33 (04) :427-441

[6] A Role for the Ca2+ Channel TRPML1 in Gastric Acid Secretion, Based on Analysis of Knockout Mice [J].

Chandra, Manjari ;

Zhou, Hua ;

Li, Qin ;

Muallem, Shmuel ;

Hofmann, Sandra L. ;

Soyombo, Abigail A. .

GASTROENTEROLOGY, 2011, 140 (03) :857-U249

[7] Mucolipins: Intracellular TRPML1-3 channels [J].

Cheng, Xiping ;

Shen, Dongbiao ;

Samie, Mohammad ;

Xu, Haoxing .

FEBS LETTERS, 2010, 584 (10) :2013-2021

[8] A shortcut to the lysosome: The mannose-6-phosphate-independent pathway [J].

Coutinho, Maria Francisca ;

Prata, Maria Joao ;

Alves, Sandra .

MOLECULAR GENETICS AND METABOLISM, 2012, 107 (03) :257-266

[9] Mannose-6-phosphate pathway: A review on its role in lysosomal function and dysfunction [J].

Coutinho, Maria Francisca ;

Prata, Maria Joao ;

Alves, Sandra .

MOLECULAR GENETICS AND METABOLISM, 2012, 105 (04) :542-550

[10]

COVER TL, 1994, J BIOL CHEM, V269, P10566

← 1 2 3 4 5 →