Bacterial Infection Drives the Expression Dynamics of microRNAs and Their isomiRs

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.

A Long Journey Ahead: Long Non-coding RNAs in Bacterial Infections

“…The lncRNAs expressed in response to TLR stimulation might belong to a core response to fine tune immune function as described for microRNAs (Siddle et al, 2015). If there are specific lncRNA candidates manipulated by bacterial effector proteins or individual virulence factors needs to be in the focus of further investigations.…”

“…In case of miRNAs it was shown that a core temporal miRNA expression pattern is induced in response to infection, shared across different bacterial species. In addition, pathogen-specific miRNAs were identified reflecting the mechanism by which certain pathogens interfere with the host response to infection (Siddle et al, 2015). Studies comparing the lncRNA expression in response to different pathogens possessing different virulence mechanisms are missing.…”

Mammalian microRNAs and long noncoding RNAs in the host-bacterial pathogen crosstalk

“…A recent analysis of the miRNAs expressed in dendritic cells in response to six different bacteria has revealed a core temporal response to infection comprising 49 miRNAs that may play an essential role in response to infection, in addition to subtle variability for each bacterium, that can be considered as a specific signature [29] (Fig 1a). Moreover, infection can induce a switch in the relative abundance of mature miRNAs deriving from the 5' and 3' arms of the precursor (a process described as "arm-switching", [30] , Fig 1b), and changes the proportion of miRNA variants (isomiRs, Fig 1c).…”

“…Moreover, infection can induce a switch in the relative abundance of mature miRNAs deriving from the 5' and 3' arms of the precursor (a process described as "arm-switching", [30] , Fig 1b), and changes the proportion of miRNA variants (isomiRs, Fig 1c). Such variability in miRNA identity is thought to affect their regulatory potential, but this aspect deserves more investigations [29].…”

IsomiRs: A New Approach to Cancer Study

“…These forms of heterogeneity in miRNAs sequence and length may affect the selecting target, miRNAs steadiness, or loading into the RNA-induced silencing complex (RISC) (2), miRNA half-life, subcellular localization (1). According to Cloonan and etal, isomiRs in biological and functional pathway such as gene targeting collaborate with canonical miRNAs (3) , therefore, suggested every changes in isomiRs proportions have functional effect on gene regulation (4). IsomiRs can be the extension of the miRNAs, which will contribute to flexible and powerful microRNAs are regulatory non-coding RNA molecules that containing about 18-24 nucleotides which involved in critical steps of many cellular processes, specifically gene expression, therefore, their deregulation can lead to human tumorigenesis.…”