Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity.

Autor:	Arunsan P; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Ittiprasert W; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Smout MJ; Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia., Cochran CJ; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Mann VH; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Chaiyadet S; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand., Karinshak SE; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Sripa B; Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand., Young ND; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Victoria, Australia., Sotillo J; Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia., Loukas A; Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia., Brindley PJ; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, United States.; Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington DC, United States., Laha T; Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2019 Jan 15; Vol. 8. Date of Electronic Publication: 2019 Jan 15.
DOI:	10.7554/eLife.41463
Abstrakt:	Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012) for cholangiocarcinoma (CCA) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam and Cambodia. We exploited this link to explore the role of the secreted growth factor termed liver fluke granulin ( Ov- GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the Ov- GRN-1 gene from the liver fluke genome. Deep sequencing of amplicon libraries from genomic DNA of gene-edited parasites revealed Cas9-catalyzed mutations within Ov- GRN-1. Gene editing resulted in rapid depletion of Ov- GRN-1 transcripts and the encoded Ov- GRN-1 protein. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, but the infection resulted in reduced pathology as evidenced by attenuated biliary hyperplasia and fibrosis. Not only does this report pioneer programmed gene-editing in parasitic flatworms, but also the striking, clinically-relevant pathophysiological phenotype confirms the role for Ov- GRN-1 in virulence morbidity during opisthorchiasis. Competing Interests: PA, WI, MS, CC, VM, SC, SK, BS, NY, JS, AL, PB, TL No competing interests declared (© 2019, Arunsan et al.)
Databáze:	MEDLINE
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