c-Myc is a novel Leishmania virulence factor by proxy that targets the host miRNA system and is essential for survival in human macrophages

Abstract

<i>Leishmania</i> species are intracellular protozoan pathogens that have evolved to successfully infect and deactivate host macrophages. How this deactivation is brought about is not completely understood. Recently, microRNAs (miRNAs) have emerged as ubiquitous regulators of macrophage gene expression that contribute to shaping the immune responses to intracellular pathogens. Conversely, several pathogens have evolved the ability to exploit host miRNA expression to manipulate host-cell phenotype. However, very little is known about the mechanisms used by intracellular pathogens to drive changes in host-cell miRNA abundance. Using miRNA expression profiling of <i>Leishmania donovani</i>-infected human macrophages, we show here that <i>Leishmania</i> infection induced a genome-wide down-regulation of host miRNAs. This repression occurred at the level of miRNA gene transcription, because the synthesis rates of primary miRNAs were significantly decreased in infected cells. miRNA repression depended on the host macrophage transcription factor c-Myc. Indeed, the expression of host c-Myc was markedly up-regulated by <i>Leishmania</i> infection, and c-Myc silencing reversed the miRNA suppression. Furthermore, c-Myc silencing significantly reduced intracellular survival of <i>Leishmania</i>, demonstrating that c-Myc is essential for <i>Leishmania</i> pathogenesis. Taken together, these findings identify c-Myc not only as being responsible for miRNA repression in <i>Leishmania</i>-infected macrophages but also as a novel and essential virulence factor by proxy that promotes <i>Leishmania</i> survival.