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Leishmania (Leishmania )  amazonensis  is an intracellular protozoan parasite responsible for the cutaneous leishmaniasis. 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  L . ( L .)  amazonensis  infection. The regulation of macrophage miRNA expression by the parasite correlates with/depends on parasite arginase activity during infection.  L . ( L .)  amazonensis (La -WT) presented significant miRNA profile alteration (27%) compared to  L . ( L .)  amazonensis  arginase knockout ( La - arg  − ) (~40%) in relation to uninfected-macrophages. We observed that 78% of the altered miRNAs were up-regulated in  La -WT infection, while only 32% were up-regulated in  La - arg  − -infected macrophages. In contrast to  La -WT, the lack of  L . ( L .)  amazonensis  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  La -WT in  La - arg  −  addback mutant. The inhibition of miR-294/ Nos 2 and miR721/ Nos2  interactions increased NOS2 expression and NO production, and reduced  L . ( L .)  amazonensis  infectivity, confirming  Nos2  as target of these miRNAs. The role of miR-294 and miR-721 in the regulation of NOS2 expression during  Leishmania  replication in infected macrophages pointing these miRNAs as potential new targets for drug development.

scientific reports

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism