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J Infect Dis. 2015 Nov 15;212(10):1636-45. doi: 10.1093/infdis/jiv291. Epub 2015 May 17.

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype.

Author information

1
Biomedical Sciences, Graduate School Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
2
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
3
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Department of Veterinary Medicine, University of Cambridge.
4
QIMR Berghofer Medical Research Institute, Brisbane School of Veterinary Sciences, University of Queensland, Gatton.
5
iThree Institute, University of Technology Sydney, Australia.
6
QIMR Berghofer Medical Research Institute, Brisbane.
7
Department of Pathology.
8
Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington D.C.
9
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand.

Abstract

BACKGROUND:

Throughout Asia, there is an unprecedented link between cholangiocarcinoma and infection with the liver fluke Opisthorchis viverrini. Multiple processes, including chronic inflammation and secretion of parasite proteins into the biliary epithelium, drive infection toward cancer. Until now, the mechanism and effects of parasite protein entry into cholangiocytes was unknown.

METHODS:

Various microscopy techniques were used to identify O. viverrini extracellular vesicles (EVs) and their internalization by human cholangiocytes. Using mass spectrometry we characterized the EV proteome and associated changes in cholangiocytes after EV uptake, and we detected EV proteins in bile of infected hamsters and humans. Cholangiocyte proliferation and interleukin 6 (IL-6) secretion was measured to assess the impact of EV internalization.

RESULTS:

EVs were identified in fluke culture medium and bile specimens from infected hosts. EVs internalized by cholangiocytes drove cell proliferation and IL-6 secretion and induced changes in protein expression associated with endocytosis, wound repair, and cancer. Antibodies to an O. viverrini tetraspanin blocked EV uptake and IL-6 secretion by cholangiocytes.

CONCLUSIONS:

This is the first time that EVs from a multicellular pathogen have been identified in host tissues. Our findings imply a role for O. viverrini EVs in pathogenesis and highlight an approach to vaccine development for this infectious cancer.

KEYWORDS:

Opisthorchis viverrini; cancer; cholangiocarcinoma; extracellular vesicles; liver fluke

PMID:
25985904
PMCID:
PMC4621255
DOI:
10.1093/infdis/jiv291
[Indexed for MEDLINE]
Free PMC Article

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