MicroRNA induction in human macrophages associated with infection with ancient and modern TB strains

Abstract

Aims and objectivesMicroRNAs are critical regulators of the mammalian immune system through the fine-tuning of gene expression. Mycobacterium tuberculosis (Mtb) can persist alive and replicate into the host due to its ability to interfere with macrophage antimicrobial mechanisms. Recent studies indicate that genetic diversity among Mtb Complex (MTBC) lineages is reflected in different clinical outcomes and epidemiological success. In this study we hypothesized that the success of modern lineages could rely, at least in part, upon their ability to alter host immune responses through the modulation of intracellular microRNAs expression. MethodsSelected strains belonging to both ancient (EAI) and modern (Haarlem and Beijing) lineages were characterized for their ability to enter, survive and replicate in human monocyte-derived macrophages (MDM). Their capacity to modulate the inflammatory immune response was analyzed in terms of cytokine secretion by means of Fluorokine MAP suspension Array System and their influence on cellular microRNAs expression by, TaqMan Low Density Arrays. ResultsInfection of human differentiated MDM by modern strains was characterized by variable phagocyte uptake, but higher intracellular growth and higher associated cytotoxicity. The release of several proinflammatory cytokines in response to strains belonging to modern lineages was significantly lower compared to strains from ancient lineages. Finally, we identified a group of microRNAs which are commonly regulated by all clinical strains and which are involved in the regulation of critical functions in host immune response; and a set of microRNAs specifically related to latency, lipid metabolism and proinflammatory cytokine release and responsiveness differentially modulated by modern versus ancient lineages. ConclusionIn this study it was observed that the genetic diversity among Mtb strains and, in particular between ancient and modern strains, reflects on several aspects of host-pathogen interaction. In particular, the modulation of specific cellular microRNAs upon MTBC infection suggests a potential role for these microRNAs in the outcome of infection and, to a major extent, to the different epidemiological success of Mtb strains.