Protection of macrophages from intracellular pathogens by miR-182-5p mimic—a gene expression meta-analysis approach

Abstract

The goals of this study were to (a) define which host genes are of particular importance during the interactions between macrophages and intracellular pathogens, and (b) use this knowledge to gain fresh, experimental understanding of how macrophage activities may be manipulated during host defense. We designed an in silico method for meta-analysis of microarray gene expression data, and used this to combine data from 16 different studies of cells in the monocyte–macrophage lineage infected with seven different pathogens. Three thousand four hundred ninety-eight genes were identified, which we call the macrophage intracellular pathogen response (macIPR) gene set. As expected, the macIPR gene set showed a strong bias toward genes previously associated with the immune response. Predicted target sites for miR-182-5p (miR-182) were strongly over-represented among macIPR genes, indicating an unexpected role for miR-182-regulatable genes during intracellular pathogenesis. We therefore transfected primary human alveolar macrophage-like monocyte-derived macrophages from multiple different donors with synthetic miR-182, and found that miR-182 overexpression (a) increases proinflammatory gene induction during infection with Francisella tularensis live vaccine strain (LVS), (b) primes macrophages for increased autophagy, and (c) enhances macrophage control of both gram negative F. tularensisLVS and gram positive Bacillus anthracisANR-1 spores. These data therefore suggest a new application for miR-182 in promoting resistance to intracellular pathogens.