Abstract
The optimal coordination of the transcriptional response of host cells to infection is essential for establishing appropriate immunological outcomes. In this context, the role of microRNAs (miRNAs) – important epigenetic regulators of gene expression – in regulating mammalian immune systems is increasingly well recognised. However, the expression dynamics of miRNAs, and that of their isoforms, in response to infection remains largely unexplored. Here, we characterized the genome-wide miRNA transcriptional responses of human dendritic cells, over time, to various mycobacteria differing in their virulence as well as to other bacteria outside the genus Mycobacterium, using small RNA-sequencing. We detected the presence of a core temporal response to infection, shared across bacteria, comprising 49 miRNAs, highlighting a set of miRNAs that may play an essential role in the regulation of basic cellular responses to stress. Despite such broadly shared expression dynamics, we identified specific elements of variation in the miRNA response to infection across bacteria, including a virulence-dependent induction of the miR-132/212 family in response to mycobacterial infections. We also found that infection has a strong impact on both the relative abundance of the miRNA hairpin arms and the expression dynamics of miRNA isoforms. That we observed broadly consistent changes in relative arm expression and isomiR distribution across bacteria suggests that this additional, internal layer of variability in miRNA responses represents an additional source of subtle miRNA-mediated regulation upon infection. Collectively, this study increases our understanding of the dynamism and role of miRNAs in response to bacterial infection, revealing novel features of their internal variability and identifying candidate miRNAs that may contribute to differences in the pathogenicity of mycobacterial infections.
Highlights
The response of host cells to microbial infection or immune activation is among the most-well studied examples of cellular responses to external stimuli
We define a set of miRNAs that play an essential role in basic cellular responses to stress and identify pathogen-specific miRNA responses that reflect mechanisms by which certain pathogens interfere with the host response to infection
This study highlights a novel aspect of miRNA expression dynamics upon infection and increases our understanding of miRNA-mediated mechanisms involved in host cellular responses to infection
Summary
The response of host cells to microbial infection or immune activation is among the most-well studied examples of cellular responses to external stimuli. This response is characterised by marked changes in gene expression [1,2,3,4,5,6], which require precise coordination to establish appropriate immunological outcomes, ensuring maximal protection against infection while avoiding tissue damage. Besides the detection of many novel miRNAs and the description of an increasingly broad array of non-canonical biogenesis pathways producing functional miRNAs [19,20,21], RNA-seq studies have highlighted the highly dynamic relative abundance of the 5p and 3p arms of the miRNA duplex, a process known as arm-switching [22]. Believed to be static and dictated by the thermodynamic and structural properties of the duplex [24,25], the choice of the dominant miRNA arm has recently been shown to be flexible across species, tissues and developmental stages [22,26,27,28,29,30,31]
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