Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1
Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glu...
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| creator | Mandal, Goutam Mandal, Srotoswati Sharma, Mansi Charret, Karen Santos Papadopoulou, Barbara Bhattacharjee, Hiranmoy Mukhopadhyay, Rita |
| description | Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species. |
| doi_str_mv | 10.1371/journal.pntd.0003500 |
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The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0003500</identifier><identifier>PMID: 25714343</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated Regions - genetics ; Antimony - chemistry ; Antimony - metabolism ; Antimony Sodium Gluconate - therapeutic use ; Antiprotozoal Agents - therapeutic use ; Aquaglyceroporins - metabolism ; Aquaporin 1 - genetics ; Cell adhesion & migration ; Cell Movement - genetics ; Colleges & universities ; Distribution ; Drug Resistance - genetics ; Drugs ; Experiments ; Gene Expression Regulation - genetics ; Genetic aspects ; Health aspects ; Humans ; Identification and classification ; Leishmania ; Leishmania - classification ; Leishmania - drug effects ; Leishmania - genetics ; Leishmaniasis ; Leishmaniasis, Cutaneous - drug therapy ; Leishmaniasis, Cutaneous - parasitology ; Leishmaniasis, Visceral - drug therapy ; Leishmaniasis, Visceral - parasitology ; Mammals ; Meglumine - therapeutic use ; Meglumine Antimoniate ; MicroRNA ; Organometallic Compounds - therapeutic use ; Parasites ; Parasitic diseases ; Properties ; RNA, Messenger - genetics ; RNA, Protozoan - genetics ; Rodents</subject><ispartof>PLoS neglected tropical diseases, 2015-02, Vol.9 (2), p.e0003500-e0003500</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Mandal et al 2015 Mandal et al</rights><rights>2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Is Driven by Post-Transcriptional Regulation of AQP1. PLoS Negl Trop Dis 9(2): e0003500. doi:10.1371/journal.pntd.0003500</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c629t-fbf1d2f2b2e5d520a50eebff53c94adf25eaf4d264e170dd6a91a83fdac620bd3</citedby><cites>FETCH-LOGICAL-c629t-fbf1d2f2b2e5d520a50eebff53c94adf25eaf4d264e170dd6a91a83fdac620bd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340957/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340957/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25714343$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Salavati, Reza</contributor><creatorcontrib>Mandal, Goutam</creatorcontrib><creatorcontrib>Mandal, Srotoswati</creatorcontrib><creatorcontrib>Sharma, Mansi</creatorcontrib><creatorcontrib>Charret, Karen Santos</creatorcontrib><creatorcontrib>Papadopoulou, Barbara</creatorcontrib><creatorcontrib>Bhattacharjee, Hiranmoy</creatorcontrib><creatorcontrib>Mukhopadhyay, Rita</creatorcontrib><title>Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.</description><subject>3' Untranslated Regions - genetics</subject><subject>Antimony - chemistry</subject><subject>Antimony - metabolism</subject><subject>Antimony Sodium Gluconate - therapeutic use</subject><subject>Antiprotozoal Agents - therapeutic use</subject><subject>Aquaglyceroporins - metabolism</subject><subject>Aquaporin 1 - genetics</subject><subject>Cell adhesion & migration</subject><subject>Cell Movement - genetics</subject><subject>Colleges & universities</subject><subject>Distribution</subject><subject>Drug Resistance - genetics</subject><subject>Drugs</subject><subject>Experiments</subject><subject>Gene Expression Regulation - genetics</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Identification and classification</subject><subject>Leishmania</subject><subject>Leishmania - classification</subject><subject>Leishmania - drug effects</subject><subject>Leishmania - genetics</subject><subject>Leishmaniasis</subject><subject>Leishmaniasis, Cutaneous - drug therapy</subject><subject>Leishmaniasis, Cutaneous - parasitology</subject><subject>Leishmaniasis, Visceral - drug therapy</subject><subject>Leishmaniasis, Visceral - parasitology</subject><subject>Mammals</subject><subject>Meglumine - therapeutic use</subject><subject>Meglumine Antimoniate</subject><subject>MicroRNA</subject><subject>Organometallic Compounds - therapeutic use</subject><subject>Parasites</subject><subject>Parasitic diseases</subject><subject>Properties</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Protozoan - genetics</subject><subject>Rodents</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqNUl2L1DAULaK46-o_EC0I4kvHJE368SIMix8LAyrqc7htbmYytElN2oH596ZOd5kBHyQPSe495-Tek5skLylZ0byk7_du8ha61WBHtSKE5IKQR8k1rXORsTIXj8_OV8mzEPaEiFpU9GlyxURJec7z62T_Y8DWYMjCvGvTpmBH0ztroEsD2mBGczDjMTU23aAJux5iKjUhVd4c0KbNMR1cGLPRgw2tN8NoXCwr9bidOpgvqdPp-vs3-jx5oqEL-GLZb5Jfnz7-vP2Sbb5-vrtdb7K2YPWY6UZTxTRrGAolGAFBEButRd7WHJRmAkFzxQqOtCRKFVBTqHKtIPJJo_Kb5PVJd-hckItNQdKiEgXj0YGIuDshlIO9HLzpwR-lAyP_BpzfSvCjaTuUijfRRA2CoeZa1Q3lwDWtaZXHDIeo9WF5bWp6VC3a6ER3IXqZsWYnt-4go_-kFmUUeLcIePd7wjDK3oQWuw4summuu6hYIRj9H6ioy6Ii1dzimxN0C7ELY7WLj7czXK55LF8QRmbU6h-ouBT2pnUWtYnxC8LbM8IOoRt3wXXT_M_hEshPwNa7EDzqB0cokfP83n-MnOdXLvMbaa_O3Xwg3Q9s_gdUdO97</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Mandal, Goutam</creator><creator>Mandal, Srotoswati</creator><creator>Sharma, Mansi</creator><creator>Charret, Karen Santos</creator><creator>Papadopoulou, Barbara</creator><creator>Bhattacharjee, Hiranmoy</creator><creator>Mukhopadhyay, Rita</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>7X8</scope><scope>7SS</scope><scope>M7N</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150201</creationdate><title>Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1</title><author>Mandal, Goutam ; Mandal, Srotoswati ; Sharma, Mansi ; Charret, Karen Santos ; Papadopoulou, Barbara ; Bhattacharjee, Hiranmoy ; Mukhopadhyay, Rita</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c629t-fbf1d2f2b2e5d520a50eebff53c94adf25eaf4d264e170dd6a91a83fdac620bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3' Untranslated Regions - genetics</topic><topic>Antimony - chemistry</topic><topic>Antimony - metabolism</topic><topic>Antimony Sodium Gluconate - therapeutic use</topic><topic>Antiprotozoal Agents - therapeutic use</topic><topic>Aquaglyceroporins - metabolism</topic><topic>Aquaporin 1 - genetics</topic><topic>Cell adhesion & migration</topic><topic>Cell Movement - genetics</topic><topic>Colleges & universities</topic><topic>Distribution</topic><topic>Drug Resistance - genetics</topic><topic>Drugs</topic><topic>Experiments</topic><topic>Gene Expression Regulation - genetics</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Identification and classification</topic><topic>Leishmania</topic><topic>Leishmania - classification</topic><topic>Leishmania - drug effects</topic><topic>Leishmania - genetics</topic><topic>Leishmaniasis</topic><topic>Leishmaniasis, Cutaneous - drug therapy</topic><topic>Leishmaniasis, Cutaneous - parasitology</topic><topic>Leishmaniasis, Visceral - drug therapy</topic><topic>Leishmaniasis, Visceral - parasitology</topic><topic>Mammals</topic><topic>Meglumine - therapeutic use</topic><topic>Meglumine Antimoniate</topic><topic>MicroRNA</topic><topic>Organometallic Compounds - therapeutic use</topic><topic>Parasites</topic><topic>Parasitic diseases</topic><topic>Properties</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Protozoan - genetics</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mandal, Goutam</creatorcontrib><creatorcontrib>Mandal, Srotoswati</creatorcontrib><creatorcontrib>Sharma, Mansi</creatorcontrib><creatorcontrib>Charret, Karen Santos</creatorcontrib><creatorcontrib>Papadopoulou, Barbara</creatorcontrib><creatorcontrib>Bhattacharjee, Hiranmoy</creatorcontrib><creatorcontrib>Mukhopadhyay, Rita</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</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>Mandal, Goutam</au><au>Mandal, Srotoswati</au><au>Sharma, Mansi</au><au>Charret, Karen Santos</au><au>Papadopoulou, Barbara</au><au>Bhattacharjee, Hiranmoy</au><au>Mukhopadhyay, Rita</au><au>Salavati, Reza</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1</atitle><jtitle>PLoS neglected tropical diseases</jtitle><addtitle>PLoS Negl Trop Dis</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>9</volume><issue>2</issue><spage>e0003500</spage><epage>e0003500</epage><pages>e0003500-e0003500</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><abstract>Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25714343</pmid><doi>10.1371/journal.pntd.0003500</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated Regions - genetics Antimony - chemistry Antimony - metabolism Antimony Sodium Gluconate - therapeutic use Antiprotozoal Agents - therapeutic use Aquaglyceroporins - metabolism Aquaporin 1 - genetics Cell adhesion & migration Cell Movement - genetics Colleges & universities Distribution Drug Resistance - genetics Drugs Experiments Gene Expression Regulation - genetics Genetic aspects Health aspects Humans Identification and classification Leishmania Leishmania - classification Leishmania - drug effects Leishmania - genetics Leishmaniasis Leishmaniasis, Cutaneous - drug therapy Leishmaniasis, Cutaneous - parasitology Leishmaniasis, Visceral - drug therapy Leishmaniasis, Visceral - parasitology Mammals Meglumine - therapeutic use Meglumine Antimoniate MicroRNA Organometallic Compounds - therapeutic use Parasites Parasitic diseases Properties RNA, Messenger - genetics RNA, Protozoan - genetics Rodents |
| title | Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1 |
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