PLoS pathogens, 2022-09, Vol.18 (9), p.e1010839-e1010839
2022
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini
- Ist Teil von
- PLoS pathogens, 2022-09, Vol.18 (9), p.e1010839-e1010839
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1010839Titel-ID: cdi_plos_journals_2725275179
- Format
- –
- Schlagworte
- Animals, Bile Duct Neoplasms - genetics, Bile Duct Neoplasms - parasitology, Bile ducts, Bile Ducts, Intrahepatic - metabolism, Bile Ducts, Intrahepatic - parasitology, Bile Ducts, Intrahepatic - pathology, Biliary tract, Biology and Life Sciences, Cancer, Carcinogens, Cell proliferation, Cholangiocarcinoma, Cholangiocarcinoma - genetics, Cholangiocarcinoma - parasitology, Chronic infection, Colorimetry, Confidence intervals, Cricetinae, CRISPR, Depletion, Development and progression, Diet, Electroporation, Epithelial cells, Epithelium, Experiments, Fasciola hepatica - genetics, Fasciola hepatica - metabolism, Fibrosis, Fluke infections, Gene expression, Gene sequencing, Genetic engineering, Genetic modification, Genomes, Genotypes, Granulin, Granulins - metabolism, gRNA, Growth factors, Hamsters, Histochemical analysis, Infections, Influence, Intercellular Signaling Peptides and Proteins, Liver, Malignancy, Medicine and Health Sciences, Morbidity, Mutation, Nitrosamine, Nitrosamines, Opisthorchiasis - complications, Opisthorchiasis - parasitology, Opisthorchiasis - pathology, Opisthorchis - genetics, Opisthorchis - metabolism, Opisthorchis viverrini, p53 Protein, Parasites, Pathogenesis, Persistent Infection, Phenotypes, Plasmids, Risk analysis, Risk factors, RNA, Guide, CRISPR-Cas Systems, Tropical diseases, Worms