Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis
Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by...
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| Veröffentlicht in: | PLoS neglected tropical diseases 2019-09, Vol.13 (9), p.e0007687 |
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| creator | Flynn, Alexander F Joyce, M Gordon Taylor, Rebekah T Bennuru, Sasisekhar Lindrose, Alyssa R Sterling, Spencer L Morris, C Paul Nutman, Thomas B Mitre, Edward |
| description | Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans. |
| doi_str_mv | 10.1371/journal.pntd.0007687 |
| format | Article |
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Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0007687</identifier><identifier>PMID: 31513587</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Albendazole ; Albendazole - pharmacology ; Animals ; Antigens ; Antigens, Helminth - blood ; Biology and Life Sciences ; Brugia malayi - drug effects ; Brugia malayi - enzymology ; Brugia malayi - immunology ; Brugia malayi - metabolism ; Care and treatment ; Disease control ; Drug development ; Drug Therapy, Combination ; Elephantiasis, Filarial - drug therapy ; Elephantiasis, Filarial - prevention & control ; Engineering and Technology ; Female ; Filariasis ; Filaricides - pharmacology ; Gene expression ; Glucuronosyltransferase ; Glucuronosyltransferase - antagonists & inhibitors ; Glucuronosyltransferase - genetics ; Glucuronosyltransferase - metabolism ; Health aspects ; Health sciences ; Humans ; Immunoglobulin E ; Immunoglobulin E - blood ; Immunoprecipitation ; Infections ; Infectious diseases ; Intestine ; Intestines - enzymology ; Luciferase ; Lymphatic diseases ; Medical research ; Medicine ; Medicine and Health Sciences ; Messenger RNA ; Metabolism ; Microfilariae - drug effects ; Movement ; mRNA ; Nematodes ; Populations ; Prevention ; Probenecid ; Probenecid - pharmacology ; Proteins ; Reduction ; Research and Analysis Methods ; RNA ; RNA, Small Interfering ; Roundworms ; siRNA ; Sulfinpyrazone ; Sulfinpyrazone - pharmacology ; Survival ; Therapeutic applications ; Tropical diseases ; UDP-glucuronosyltransferase ; Vaccines ; Vector-borne diseases ; Worms</subject><ispartof>PLoS neglected tropical diseases, 2019-09, Vol.13 (9), p.e0007687</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-141c5200a46cc0b812c2d42cd8de4a372e182ba33e6ec28993fd099125a8cc073</citedby><cites>FETCH-LOGICAL-c624t-141c5200a46cc0b812c2d42cd8de4a372e182ba33e6ec28993fd099125a8cc073</cites><orcidid>0000-0001-7506-3266 ; 0000-0002-6808-7232 ; 0000-0003-2372-3677 ; 0000-0002-0348-8983 ; 0000-0002-0952-1975</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742224/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742224/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31513587$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Makepeace, Benjamin L</contributor><creatorcontrib>Flynn, Alexander F</creatorcontrib><creatorcontrib>Joyce, M Gordon</creatorcontrib><creatorcontrib>Taylor, Rebekah T</creatorcontrib><creatorcontrib>Bennuru, Sasisekhar</creatorcontrib><creatorcontrib>Lindrose, Alyssa R</creatorcontrib><creatorcontrib>Sterling, Spencer L</creatorcontrib><creatorcontrib>Morris, C Paul</creatorcontrib><creatorcontrib>Nutman, Thomas B</creatorcontrib><creatorcontrib>Mitre, Edward</creatorcontrib><title>Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.</description><subject>Albendazole</subject><subject>Albendazole - pharmacology</subject><subject>Animals</subject><subject>Antigens</subject><subject>Antigens, Helminth - blood</subject><subject>Biology and Life Sciences</subject><subject>Brugia malayi - drug effects</subject><subject>Brugia malayi - enzymology</subject><subject>Brugia malayi - immunology</subject><subject>Brugia malayi - metabolism</subject><subject>Care and treatment</subject><subject>Disease control</subject><subject>Drug development</subject><subject>Drug Therapy, Combination</subject><subject>Elephantiasis, Filarial - drug therapy</subject><subject>Elephantiasis, Filarial - prevention & control</subject><subject>Engineering and Technology</subject><subject>Female</subject><subject>Filariasis</subject><subject>Filaricides - pharmacology</subject><subject>Gene expression</subject><subject>Glucuronosyltransferase</subject><subject>Glucuronosyltransferase - 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pharmacology</subject><subject>Survival</subject><subject>Therapeutic applications</subject><subject>Tropical diseases</subject><subject>UDP-glucuronosyltransferase</subject><subject>Vaccines</subject><subject>Vector-borne diseases</subject><subject>Worms</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkttqGzEQhpfS0qRp36C0gkLpjV0dVnu4KYT0FAi0F821GGtnbRmt5EragN--2ngT7BJ0ISF9_z-jmSmKt4wumajZ560fgwO73LnULSmlddXUz4pz1gq54LWQz4_OZ8WrGLeUylY27GVxJphkQjb1eTFeu4QxmexEbr_-XqztqMfgnY97mwK42GOAiAQiAbLzCV0yGU0Q1phI7wNJGyQpIKQhvxFwHdkFvJs474jvid0Puw0ko0lvLAQD0cTXxYsebMQ3835R3H7_9ufq5-Lm14_rq8ubha54mRasZFpySqGstKarhnHNu5LrrumwBFFzZA1fgRBYoeZN24q-o23LuIQmC2pxUbw_-O6sj2quWFRc0OxfU9lk4vpAdB62ahfMAGGvPBh1f-HDWkHIyVtUmiPgZEulKJHppsYSNetXFLqVbqvs9WWONq4G7HSuQQB7Ynr64sxGrf2dquqSc15mg0-zQfB_x9wWNZio0Vpw6MecN29pSxshZUY__Ic-_buZWkP-gHG9z3H1ZKouKypoy8t7avkElVeHg9HeYW4cngo-Hgk2CDZtorfj1PJ4CpYHUAcfY8D-sRiMqmmKH7JW0xSreYqz7N1xIR9FD2Mr_gHKvfET</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Flynn, Alexander F</creator><creator>Joyce, M Gordon</creator><creator>Taylor, Rebekah T</creator><creator>Bennuru, Sasisekhar</creator><creator>Lindrose, Alyssa R</creator><creator>Sterling, Spencer L</creator><creator>Morris, C Paul</creator><creator>Nutman, Thomas B</creator><creator>Mitre, Edward</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-7506-3266</orcidid><orcidid>https://orcid.org/0000-0002-6808-7232</orcidid><orcidid>https://orcid.org/0000-0003-2372-3677</orcidid><orcidid>https://orcid.org/0000-0002-0348-8983</orcidid><orcidid>https://orcid.org/0000-0002-0952-1975</orcidid></search><sort><creationdate>20190901</creationdate><title>Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis</title><author>Flynn, Alexander F ; Joyce, M Gordon ; Taylor, Rebekah T ; Bennuru, Sasisekhar ; Lindrose, Alyssa R ; Sterling, Spencer L ; Morris, C Paul ; Nutman, Thomas B ; Mitre, Edward</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c624t-141c5200a46cc0b812c2d42cd8de4a372e182ba33e6ec28993fd099125a8cc073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Albendazole</topic><topic>Albendazole - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS neglected tropical diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flynn, Alexander F</au><au>Joyce, M Gordon</au><au>Taylor, Rebekah T</au><au>Bennuru, Sasisekhar</au><au>Lindrose, Alyssa R</au><au>Sterling, Spencer L</au><au>Morris, C Paul</au><au>Nutman, Thomas B</au><au>Mitre, Edward</au><au>Makepeace, Benjamin L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis</atitle><jtitle>PLoS neglected tropical diseases</jtitle><addtitle>PLoS Negl Trop Dis</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>13</volume><issue>9</issue><spage>e0007687</spage><pages>e0007687-</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><abstract>Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31513587</pmid><doi>10.1371/journal.pntd.0007687</doi><orcidid>https://orcid.org/0000-0001-7506-3266</orcidid><orcidid>https://orcid.org/0000-0002-6808-7232</orcidid><orcidid>https://orcid.org/0000-0003-2372-3677</orcidid><orcidid>https://orcid.org/0000-0002-0348-8983</orcidid><orcidid>https://orcid.org/0000-0002-0952-1975</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1935-2735 |
| ispartof | PLoS neglected tropical diseases, 2019-09, Vol.13 (9), p.e0007687 |
| issn | 1935-2735 1935-2727 1935-2735 |
| language | eng |
| recordid | cdi_plos_journals_2306247058 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access |
| subjects | Albendazole Albendazole - pharmacology Animals Antigens Antigens, Helminth - blood Biology and Life Sciences Brugia malayi - drug effects Brugia malayi - enzymology Brugia malayi - immunology Brugia malayi - metabolism Care and treatment Disease control Drug development Drug Therapy, Combination Elephantiasis, Filarial - drug therapy Elephantiasis, Filarial - prevention & control Engineering and Technology Female Filariasis Filaricides - pharmacology Gene expression Glucuronosyltransferase Glucuronosyltransferase - antagonists & inhibitors Glucuronosyltransferase - genetics Glucuronosyltransferase - metabolism Health aspects Health sciences Humans Immunoglobulin E Immunoglobulin E - blood Immunoprecipitation Infections Infectious diseases Intestine Intestines - enzymology Luciferase Lymphatic diseases Medical research Medicine Medicine and Health Sciences Messenger RNA Metabolism Microfilariae - drug effects Movement mRNA Nematodes Populations Prevention Probenecid Probenecid - pharmacology Proteins Reduction Research and Analysis Methods RNA RNA, Small Interfering Roundworms siRNA Sulfinpyrazone Sulfinpyrazone - pharmacology Survival Therapeutic applications Tropical diseases UDP-glucuronosyltransferase Vaccines Vector-borne diseases Worms |
| title | Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T04%3A57%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Intestinal%20UDP-glucuronosyltransferase%20as%20a%20potential%20target%20for%20the%20treatment%20and%20prevention%20of%20lymphatic%20filariasis&rft.jtitle=PLoS%20neglected%20tropical%20diseases&rft.au=Flynn,%20Alexander%20F&rft.date=2019-09-01&rft.volume=13&rft.issue=9&rft.spage=e0007687&rft.pages=e0007687-&rft.issn=1935-2735&rft.eissn=1935-2735&rft_id=info:doi/10.1371/journal.pntd.0007687&rft_dat=%3Cgale_plos_%3EA603092458%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2306247058&rft_id=info:pmid/31513587&rft_galeid=A603092458&rft_doaj_id=oai_doaj_org_article_c2eaecc070534e1c87e4ec1fb0adbc96&rfr_iscdi=true |