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J Biol Chem. 2018 Aug 17;293(33):12805-12819. doi: 10.1074/jbc.RA118.002462. Epub 2018 Jun 22.

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

Author information

1
From the Division of Infectious Diseases, Department of Medicine, Vancouver Coastal Health Research Institute, Vancouver, British Columbia V5Z 1M9 and.
2
the Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 3J5, Canada.
3
From the Division of Infectious Diseases, Department of Medicine, Vancouver Coastal Health Research Institute, Vancouver, British Columbia V5Z 1M9 and nreiner@mail.ubc.ca.

Abstract

Leishmania 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 Leishmania donovani-infected human macrophages, we show here that Leishmania 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 Leishmania infection, and c-Myc silencing reversed the miRNA suppression. Furthermore, c-Myc silencing significantly reduced intracellular survival of Leishmania, demonstrating that c-Myc is essential for Leishmania pathogenesis. Taken together, these findings identify c-Myc not only as being responsible for miRNA repression in Leishmania-infected macrophages but also as a novel and essential virulence factor by proxy that promotes Leishmania survival.

KEYWORDS:

Leishmania; Myc (c-Myc); infection; macrophage; microRNA (miRNA); microRNA biogenesis; protozoan; transcription regulation; virulence factor

PMID:
29934305
PMCID:
PMC6102154
DOI:
10.1074/jbc.RA118.002462
[Indexed for MEDLINE]
Free PMC Article

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