Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini.
Animals
Bile Duct Neoplasms
/ genetics
Bile Ducts, Intrahepatic
/ metabolism
Cholangiocarcinoma
/ genetics
Cricetinae
Fasciola hepatica
/ genetics
Fibrosis
Granulins
/ metabolism
Intercellular Signaling Peptides and Proteins
Nitrosamines
Opisthorchiasis
/ complications
Opisthorchis
/ genetics
Persistent Infection
RNA, Guide, Kinetoplastida
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
18
01
2022
accepted:
29
08
2022
revised:
04
10
2022
pubmed:
23
9
2022
medline:
7
10
2022
entrez:
22
9
2022
Statut:
epublish
Résumé
Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA) in the Mekong Basin countries of Thailand, Lao PDR, Vietnam, Myanmar and Cambodia. Using a novel model of CCA, involving infection with gene-edited liver flukes in the hamster during concurrent exposure to dietary nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We derived RNA-guided gene knockout flukes (ΔOv-grn-1) using CRISPR/Cas9/gRNA materials delivered by electroporation. Genome sequencing confirmed programmed Cas9-catalyzed mutations of the targeted genes, which was accompanied by rapid depletion of transcripts and the proteins they encode. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes. However, less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control gene-edited and mock-edited parasites. Specifically, immuno- and colorimetric-histochemical analysis of livers revealed markedly less periductal fibrosis surrounding the flukes and less fibrosis globally within the hepatobiliary tract during infection with ΔOv-grn-1 genotype worms, minimal biliary epithelial cell proliferation, and significantly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high-grade CCA compared to controls. The clinically relevant, pathophysiological phenotype of the hepatobiliary tract confirmed a role for this secreted growth factor in malignancy and morbidity during opisthorchiasis.
Identifiants
pubmed: 36137145
doi: 10.1371/journal.ppat.1010839
pii: PPATHOGENS-D-22-00097
pmc: PMC9531791
doi:
Substances chimiques
Granulins
0
Intercellular Signaling Peptides and Proteins
0
Nitrosamines
0
RNA, Guide
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010839Subventions
Organisme : NCI NIH HHS
ID : R01 CA164719
Pays : United States
Organisme : Wellcome Trust
ID : 107475/Z/15/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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