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The parasite replicates inside mammalian macrophage to establish infection. Host-pathogen interactions result in microRNA-mediated post-transcriptional regulation of host genes involved in inflammatory immune response. We analyzed macrophage miRNA profiles during<jats:italic>L<\/jats:italic>. (<jats:italic>L<\/jats:italic>.)<jats:italic>amazonensis<\/jats:italic>infection. The regulation of macrophage miRNA expression by the parasite correlates with\/depends on parasite arginase activity during infection.<jats:italic>L<\/jats:italic>. (<jats:italic>L<\/jats:italic>.)<jats:italic>amazonensis (La<\/jats:italic>-WT) presented significant miRNA profile alteration (27%) compared to<jats:italic>L<\/jats:italic>. (<jats:italic>L<\/jats:italic>.)<jats:italic>amazonensis<\/jats:italic>arginase knockout (<jats:italic>La<\/jats:italic>-<jats:italic>arg<\/jats:italic><jats:sup>\u2212<\/jats:sup>) (~40%) in relation to uninfected-macrophages. We observed that 78% of the altered miRNAs were up-regulated in<jats:italic>La<\/jats:italic>-WT infection, while only 32% were up-regulated in<jats:italic>La<\/jats:italic>-<jats:italic>arg<\/jats:italic><jats:sup>\u2212<\/jats:sup>-infected macrophages. In contrast to<jats:italic>La<\/jats:italic>-WT, the lack of<jats:italic>L<\/jats:italic>. (<jats:italic>L<\/jats:italic>.)<jats:italic>amazonensis<\/jats:italic>arginase led to the inhibition of miR-294 and miR-721 expression. The expression of miR-294 and miR-721 was recovered to levels similar to<jats:italic>La<\/jats:italic>-WT in<jats:italic>La<\/jats:italic>-<jats:italic>arg<\/jats:italic><jats:sup>\u2212<\/jats:sup>addback mutant. The inhibition of miR-294\/<jats:italic>Nos<\/jats:italic>2 and miR721\/<jats:italic>Nos2<\/jats:italic>interactions increased NOS2 expression and NO production, and reduced<jats:italic>L<\/jats:italic>. (<jats:italic>L<\/jats:italic>.)<jats:italic>amazonensis<\/jats:italic>infectivity, confirming<jats:italic>Nos2<\/jats:italic>as target of these miRNAs. The role of miR-294 and miR-721 in the regulation of NOS2 expression during<jats:italic>Leishmania<\/jats:italic>replication in infected macrophages pointing these miRNAs as potential new targets for drug development.<\/jats:p>","DOI":"10.1038\/srep44141","type":"journal-article","created":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T10:08:45Z","timestamp":1489054125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism"],"prefix":"10.1038","volume":"7","author":[{"given":"Sandra Marcia","family":"Muxel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Fernanda","family":"Laranjeira-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Andrade","family":"Zampieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile Maria","family":"Floeter-Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,9]]},"reference":[{"key":"BFsrep44141_CR1","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1111\/j.1462-5822.2008.01146.x","volume":"10","author":"C Bogdan","year":"2008","unstructured":"Bogdan, C. 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