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Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity
Infection with the food-borne liver fluke 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 expl...
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| Published in: | eLife 2019-01, Vol.8 |
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| creator | Arunsan, Patpicha Ittiprasert, Wannaporn Smout, Michael J Cochran, Christina J Mann, Victoria H Chaiyadet, Sujittra Karinshak, Shannon E Sripa, Banchob Young, Neil David Sotillo, Javier Loukas, Alex Brindley, Paul J Laha, Thewarach |
| description | Infection with the food-borne liver fluke
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 (
GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the
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
GRN-1. Gene editing resulted in rapid depletion of
GRN-1 transcripts and the encoded
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
GRN-1 in virulence morbidity during opisthorchiasis. |
| doi_str_mv | 10.7554/eLife.41463 |
| format | article |
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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 (
GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the
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
GRN-1. Gene editing resulted in rapid depletion of
GRN-1 transcripts and the encoded
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
GRN-1 in virulence morbidity during opisthorchiasis.</description><identifier>ISSN: 2050-084X</identifier><identifier>EISSN: 2050-084X</identifier><identifier>DOI: 10.7554/eLife.41463</identifier><identifier>PMID: 30644359</identifier><language>eng</language><publisher>England: eLife Sciences Publications Ltd</publisher><subject>Animals ; Bile ; Bile Ducts, Intrahepatic - parasitology ; Bile Ducts, Intrahepatic - pathology ; Biliary tract ; Carcinogenesis - pathology ; carcinogenic ; Cell Line ; Cell Proliferation ; Cholangiocarcinoma ; Chronic Disease ; Cricetinae ; CRISPR ; CRISPR-Cas Systems - genetics ; Deoxyribonucleic acid ; DNA ; DNA sequencing ; Efficiency ; Fibrosis ; Gene Editing ; Gene Expression Regulation ; Gene Knockout Techniques ; Genome ; Genome editing ; Genomes ; Granulin ; Granulins - genetics ; Granulins - metabolism ; Growth factors ; Humans ; Hyperplasia ; Infections ; Liver ; Medicine ; Microbiology and Infectious Disease ; Morbidity ; Mutation ; Mutation - genetics ; Opisthorchiasis - genetics ; Opisthorchiasis - parasitology ; Opisthorchiasis - pathology ; Opisthorchis - pathogenicity ; Opisthorchis viverrini ; Parasites ; Phenotypes ; Public health ; River basins ; Rivers ; Virulence ; Wound Healing</subject><ispartof>eLife, 2019-01, Vol.8</ispartof><rights>2019, Arunsan et al.</rights><rights>2019, Arunsan et al. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019, Arunsan et al 2019 Arunsan et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-6381dce44bc82f5acf2bd5a72b6017ddfc30d53ca61dbb433fb3fe0fb5b8092e3</citedby><cites>FETCH-LOGICAL-c541t-6381dce44bc82f5acf2bd5a72b6017ddfc30d53ca61dbb433fb3fe0fb5b8092e3</cites><orcidid>0000-0001-9411-8883 ; 0000-0002-2079-0973 ; 0000-0001-8756-229X ; 0000-0003-1765-0002 ; 0000-0002-1443-7233 ; 0000-0001-6937-0112</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2186976267/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2186976267?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25731,27901,27902,36989,44566,53766,53768,74869</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30644359$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arunsan, Patpicha</creatorcontrib><creatorcontrib>Ittiprasert, Wannaporn</creatorcontrib><creatorcontrib>Smout, Michael J</creatorcontrib><creatorcontrib>Cochran, Christina J</creatorcontrib><creatorcontrib>Mann, Victoria H</creatorcontrib><creatorcontrib>Chaiyadet, Sujittra</creatorcontrib><creatorcontrib>Karinshak, Shannon E</creatorcontrib><creatorcontrib>Sripa, Banchob</creatorcontrib><creatorcontrib>Young, Neil David</creatorcontrib><creatorcontrib>Sotillo, Javier</creatorcontrib><creatorcontrib>Loukas, Alex</creatorcontrib><creatorcontrib>Brindley, Paul J</creatorcontrib><creatorcontrib>Laha, Thewarach</creatorcontrib><title>Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity</title><title>eLife</title><addtitle>Elife</addtitle><description>Infection with the food-borne liver fluke
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 (
GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the
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
GRN-1. Gene editing resulted in rapid depletion of
GRN-1 transcripts and the encoded
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
GRN-1 in virulence morbidity during opisthorchiasis.</description><subject>Animals</subject><subject>Bile</subject><subject>Bile Ducts, Intrahepatic - parasitology</subject><subject>Bile Ducts, Intrahepatic - pathology</subject><subject>Biliary tract</subject><subject>Carcinogenesis - pathology</subject><subject>carcinogenic</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cholangiocarcinoma</subject><subject>Chronic Disease</subject><subject>Cricetinae</subject><subject>CRISPR</subject><subject>CRISPR-Cas Systems - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA sequencing</subject><subject>Efficiency</subject><subject>Fibrosis</subject><subject>Gene Editing</subject><subject>Gene Expression Regulation</subject><subject>Gene Knockout Techniques</subject><subject>Genome</subject><subject>Genome editing</subject><subject>Genomes</subject><subject>Granulin</subject><subject>Granulins - genetics</subject><subject>Granulins - metabolism</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Infections</subject><subject>Liver</subject><subject>Medicine</subject><subject>Microbiology and Infectious Disease</subject><subject>Morbidity</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Opisthorchiasis - genetics</subject><subject>Opisthorchiasis - parasitology</subject><subject>Opisthorchiasis - pathology</subject><subject>Opisthorchis - pathogenicity</subject><subject>Opisthorchis viverrini</subject><subject>Parasites</subject><subject>Phenotypes</subject><subject>Public health</subject><subject>River basins</subject><subject>Rivers</subject><subject>Virulence</subject><subject>Wound Healing</subject><issn>2050-084X</issn><issn>2050-084X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNpVkc1rFDEYhwdRbKk9eZcBjzI1mXxM5iJIUVtY0IOCt_Dma5vdmWTNJAv9783utqXNJSF58rxv8mua9xhdDYzRz3blnb2imHLyqjnvEUMdEvTv62frs-ZyWTaojoEKgce3zRlBnFLCxvNm_yvFdYJ5tqbdhqi3seR2Lhmyj6GNrp383qbWTWVr2wqGMvnQQs42FMh2afc-lckGbQ-wD87qw83OB1N0dd7ZHeSo_OQh3bdzTMobn-_fNW8cTIu9fJgvmj_fv_2-vulWP3_cXn9ddZpRnDtOBDbaUqq06B0D7XplGAy94ggPxjhNkGFEA8dGKUqIU8RZ5BRTAo29JRfN7clrImzkLvm5tiEjeHnciGktIWWvJyvJyJVmrh8pQtQBFkxzwkAA9KAIE9X15eTaFVW_S9uQE0wvpC9Pgr-T67iXVcPwyKrg44MgxX_FLlluYkmhvl_2WPBx4D0fKvXpROkUlyVZ91QBI3nIXB4zl8fMK_3heVNP7GPC5D9Rj6y0</recordid><startdate>20190115</startdate><enddate>20190115</enddate><creator>Arunsan, Patpicha</creator><creator>Ittiprasert, Wannaporn</creator><creator>Smout, Michael J</creator><creator>Cochran, Christina J</creator><creator>Mann, Victoria H</creator><creator>Chaiyadet, Sujittra</creator><creator>Karinshak, Shannon E</creator><creator>Sripa, Banchob</creator><creator>Young, Neil David</creator><creator>Sotillo, Javier</creator><creator>Loukas, Alex</creator><creator>Brindley, Paul J</creator><creator>Laha, Thewarach</creator><general>eLife Sciences Publications Ltd</general><general>eLife Sciences Publications, Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9411-8883</orcidid><orcidid>https://orcid.org/0000-0002-2079-0973</orcidid><orcidid>https://orcid.org/0000-0001-8756-229X</orcidid><orcidid>https://orcid.org/0000-0003-1765-0002</orcidid><orcidid>https://orcid.org/0000-0002-1443-7233</orcidid><orcidid>https://orcid.org/0000-0001-6937-0112</orcidid></search><sort><creationdate>20190115</creationdate><title>Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity</title><author>Arunsan, Patpicha ; Ittiprasert, Wannaporn ; Smout, Michael J ; Cochran, Christina J ; Mann, Victoria H ; Chaiyadet, Sujittra ; Karinshak, Shannon E ; Sripa, Banchob ; Young, Neil David ; Sotillo, Javier ; Loukas, Alex ; Brindley, Paul J ; Laha, Thewarach</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-6381dce44bc82f5acf2bd5a72b6017ddfc30d53ca61dbb433fb3fe0fb5b8092e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Bile</topic><topic>Bile Ducts, Intrahepatic - parasitology</topic><topic>Bile Ducts, Intrahepatic - pathology</topic><topic>Biliary tract</topic><topic>Carcinogenesis - pathology</topic><topic>carcinogenic</topic><topic>Cell Line</topic><topic>Cell Proliferation</topic><topic>Cholangiocarcinoma</topic><topic>Chronic Disease</topic><topic>Cricetinae</topic><topic>CRISPR</topic><topic>CRISPR-Cas Systems - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA sequencing</topic><topic>Efficiency</topic><topic>Fibrosis</topic><topic>Gene Editing</topic><topic>Gene Expression Regulation</topic><topic>Gene Knockout Techniques</topic><topic>Genome</topic><topic>Genome editing</topic><topic>Genomes</topic><topic>Granulin</topic><topic>Granulins - genetics</topic><topic>Granulins - metabolism</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Infections</topic><topic>Liver</topic><topic>Medicine</topic><topic>Microbiology and Infectious Disease</topic><topic>Morbidity</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Opisthorchiasis - genetics</topic><topic>Opisthorchiasis - parasitology</topic><topic>Opisthorchiasis - pathology</topic><topic>Opisthorchis - pathogenicity</topic><topic>Opisthorchis viverrini</topic><topic>Parasites</topic><topic>Phenotypes</topic><topic>Public health</topic><topic>River basins</topic><topic>Rivers</topic><topic>Virulence</topic><topic>Wound Healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arunsan, Patpicha</creatorcontrib><creatorcontrib>Ittiprasert, Wannaporn</creatorcontrib><creatorcontrib>Smout, Michael J</creatorcontrib><creatorcontrib>Cochran, Christina J</creatorcontrib><creatorcontrib>Mann, Victoria H</creatorcontrib><creatorcontrib>Chaiyadet, Sujittra</creatorcontrib><creatorcontrib>Karinshak, Shannon E</creatorcontrib><creatorcontrib>Sripa, Banchob</creatorcontrib><creatorcontrib>Young, Neil David</creatorcontrib><creatorcontrib>Sotillo, Javier</creatorcontrib><creatorcontrib>Loukas, Alex</creatorcontrib><creatorcontrib>Brindley, Paul J</creatorcontrib><creatorcontrib>Laha, Thewarach</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>eLife</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arunsan, Patpicha</au><au>Ittiprasert, Wannaporn</au><au>Smout, Michael J</au><au>Cochran, Christina J</au><au>Mann, Victoria H</au><au>Chaiyadet, Sujittra</au><au>Karinshak, Shannon E</au><au>Sripa, Banchob</au><au>Young, Neil David</au><au>Sotillo, Javier</au><au>Loukas, Alex</au><au>Brindley, Paul J</au><au>Laha, Thewarach</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity</atitle><jtitle>eLife</jtitle><addtitle>Elife</addtitle><date>2019-01-15</date><risdate>2019</risdate><volume>8</volume><issn>2050-084X</issn><eissn>2050-084X</eissn><abstract>Infection with the food-borne liver fluke
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 (
GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the
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
GRN-1. Gene editing resulted in rapid depletion of
GRN-1 transcripts and the encoded
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
GRN-1 in virulence morbidity during opisthorchiasis.</abstract><cop>England</cop><pub>eLife Sciences Publications Ltd</pub><pmid>30644359</pmid><doi>10.7554/eLife.41463</doi><orcidid>https://orcid.org/0000-0001-9411-8883</orcidid><orcidid>https://orcid.org/0000-0002-2079-0973</orcidid><orcidid>https://orcid.org/0000-0001-8756-229X</orcidid><orcidid>https://orcid.org/0000-0003-1765-0002</orcidid><orcidid>https://orcid.org/0000-0002-1443-7233</orcidid><orcidid>https://orcid.org/0000-0001-6937-0112</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 2050-084X |
| ispartof | eLife, 2019-01, Vol.8 |
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| language | eng |
| recordid | cdi_doaj_primary_oai_doaj_org_article_396bc5f294004fa185c635a8aa2ab358 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Animals Bile Bile Ducts, Intrahepatic - parasitology Bile Ducts, Intrahepatic - pathology Biliary tract Carcinogenesis - pathology carcinogenic Cell Line Cell Proliferation Cholangiocarcinoma Chronic Disease Cricetinae CRISPR CRISPR-Cas Systems - genetics Deoxyribonucleic acid DNA DNA sequencing Efficiency Fibrosis Gene Editing Gene Expression Regulation Gene Knockout Techniques Genome Genome editing Genomes Granulin Granulins - genetics Granulins - metabolism Growth factors Humans Hyperplasia Infections Liver Medicine Microbiology and Infectious Disease Morbidity Mutation Mutation - genetics Opisthorchiasis - genetics Opisthorchiasis - parasitology Opisthorchiasis - pathology Opisthorchis - pathogenicity Opisthorchis viverrini Parasites Phenotypes Public health River basins Rivers Virulence Wound Healing |
| title | Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity |
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