维维里尼阿匹索氏菌
肝吸虫
生物
阿片吸虫病
胆道
奥皮斯托奇斯
病理
癌症研究
免疫学
内科学
医学
蠕虫
作者
Sujittra Chaiyadet,Sirikachorn Tangkawattana,Michael Smout,Wannaporn Ittiprasert,Victoria H. Mann,Raksawan Deenonpoe,Patpicha Arunsan,Alex Loukas,Paul J. Brindley,Thewarach Laha
出处
期刊:PLOS Pathogens
[Public Library of Science]
日期:2022-09-22
卷期号:18 (9): e1010839-e1010839
被引量:7
标识
DOI:10.1371/journal.ppat.1010839
摘要
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.
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