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

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

Nucleolar c‐Myc recruitment by a Vibrio T3SS effector promotes host cell proliferation and bacterial virulence

“…Additional studies elucidating the biochemical and structural bases for the VgpA‐mediated increase in EBP2 binding to c‐Myc and enhanced stability of c‐Myc will be valuable, given the fundamental role of c‐Myc in controlling cell growth. Also, although pathogen manipulation of c‐Myc expression levels has been described (Borth et al , 2011; Colineau et al , 2018), effector‐mediated alteration in c‐Myc localization has not.…”

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

“…Some studies corroborate the integration of the transcription factors and miRNA regulation of host immune responses. L. donovani increases the levels of the c-Myc transcription factor in human MDMs, leading to an upregulation of DROSHA and a downregulation of miRNAs let-7a, miR-151, miR-34a, miR-98, miR-148b, and miR-378a, while c-Myc knockdown reverts the expression regulation pattern of these molecules and attenuates parasite survival [93]. c-Myc overexpression sustains M2 polarization, a characteristic of human tumor-associated macrophages (TAMs), and regulates the expression of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9), HIF-1α, and transforming growth factor beta (TGF-β).…”

Leishmania regulates host macrophage miRNAs expression by engaging transcription factor c-Myc

“…S2D in Ref. 50 ), a number of cellular pathways previously implicated in Leishmania pathogenesis were identified, such as the "MAPK signaling pathway," "regulation of actin cytoskeleton," and "endocytosis.…”