The mammalian microRNA response to bacterial infections

Eulálio, Ana; Schulte, Leon N.; Vogel, Jörg

doi:10.4161/rna.20018

Cited by 172 publications

(143 citation statements)

References 70 publications

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“…Also in the eukaryotic cell many non-coding transcripts are known to fulfill regulatory functions, and this includes the orchestration of the immune response upon pathogenic attack: In various cell types representatives of the miRNA family have been shown to regulate among others the expression of key immune genes, cell-cycle genes or enzymes involved in oxidative stress (reviewed in Eulalio et al, 2012). For instance, the conserved miR-146 and miR-155, whose expression is induced upon Toll-like receptor 4 (TLR4) stimulation by bacterial LPS (Taganov et al, 2006), feedback to regulate TLR4 signaling in a non-redundant manner .…”

Section: Non-coding Rnas Involved In Virulence Infection and Immunitymentioning

confidence: 99%

Dual RNA-seq of pathogen and host

2012

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SummaryThe infection of a eukaryotic host cell by a bacterial pathogen is one of the most intimate examples of cross-kingdom interactions in biology. Infection processes are highly relevant from both a basic research as well as a clinical point of view. Sophisticated mechanisms have evolved in the pathogen to manipulate the host response and vice versa host cells have developed a wide range of anti-microbial defense strategies to combat bacterial invasion and clear infections.However, it is this diversity and complexity that makes infection research so challenging to technically address as common approaches have either been optimized for bacterial or eukaryotic organisms. Instead, methods are required that are able to deal with the often dramatic discrepancy between host and pathogen with respect to various cellular properties and processes. One class of cellular macromolecules that exemplify this host-pathogen heterogeneity is given by their transcriptomes: Bacterial transcripts differ from their eukaryotic counterparts in many aspects that involve both quantitative and qualitative traits. The entity of RNA transcripts present in a cell is of paramount interest as it reflects the cell's physiological state under the given condition. Genome-wide transcriptomic techniques such as RNA-seq have therefore been used for single-organism analyses for several years, but their applicability has been limited for infection studies.The present work describes the establishment of a novel transcriptomic approach for infection biology which we have termed "Dual RNA-seq". Using this technology, it was intended to shed light particularly on the contribution of non-protein-encoding transcripts to virulence, as these classes have mostly evaded previous infection studies due to the lack of suitable methods. The performance of Dual RNA-seq was evaluated in an in vitro infection model based on the important facultative intracellular pathogen Salmonella enterica serovar Typhimurium and different human cell lines. Dual RNA-seq was found to be capable of capturing all major bacterial and human transcript classes and proved reproducible. During the course of these experiments, a previously largely uncharacterized bacterial small non-coding RNA (sRNA), referred to as STnc440, was identified as one of the most strongly induced genes in intracellular Salmonella.Interestingly, while inhibition of STnc440 expression has been previously shown to cause a virulence defect in different animal models of Salmonellosis, the underlying molecular mechanisms have remained obscure. Here, classical genetics, transcriptomics and biochemical assays proposed a complex model of Salmonella gene expression control that is orchestrated by this sRNA. In particular, STnc440 was found to be involved in the regulation of multiple bacterial target mRNAs by direct base pair interaction with consequences for Salmonella virulence and

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Section: Non-coding Rnas Involved In Virulence Infection and Immunitymentioning

confidence: 99%

Dual RNA-seq of pathogen and host

2012

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“…Recent investigations suggest that distinct miRNAs play a role in the maintenance of immune homeostasis and the induction of immune defense (11). Moreover, evidence has shown that certain miRNAs are involved in protection against bacterial infections (12). However, their propensity to tailor the trafficking of immune cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

et al. 2013

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The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223 -/-mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223 -/-animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

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“…This analysis revealed a common set of miRNAs as the key players in the host innate immune response against bacteria, specifically miR-146, miR-155, miR-21, miR-125 and let-7. These miRNAs were shown to be regulated upon infection with various bacterial pathogens, including Helicobacter pylori, Listeria monocytogenes, Francisella tularensis, Salmonella enterica and Mycobacteria species 9,10 . Importantly, while the altered expression of several host miRNAs has been described as part of the immune response to bacterial infections, less is known about the functional role of miRNAs during the infection process.…”

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confidence: 99%

“…Misregulation of miRNA expression has been linked to several pathologies, including cancer, cardiovascular diseases and immune-related disorders 4,6,7 . In addition to their well-established functions in physiological and pathological eukaryotic cell processes, it is becoming clear that miRNAs also play crucial roles during infection by viruses 8 and bacterial pathogens 9,10 .…”

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Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

et al. 2014

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Increasing evidence suggests an important role for miRNAs in the molecular interplay\ud between bacterial pathogens and host cells. Here we perform a fluorescence microscopybased\ud screen using a library of miRNA mimics and demonstrate that miRNAs modulate\ud Salmonella infection. Several members of the miR-15 miRNA family were among the\ud 17 miRNAs that more efficiently inhibit Salmonella infection. We discovered that these\ud miRNAs are downregulated during Salmonella infection, through the inhibition of the\ud transcription factor E2F1. Analysis of miR-15 family targets revealed that derepression of\ud cyclin D1 and the consequent promotion of G1/S transition are crucial for Salmonella\ud intracellular proliferation. In addition, Salmonella induces G2/M cell cycle arrest in infected\ud cells, further promoting its replication. Overall, these findings uncover a mechanism whereby\ud Salmonella renders host cells more susceptible to infection by controlling cell cycle\ud progression through the active modulation of host cell miRNAs

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The mammalian microRNA response to bacterial infections

Cited by 172 publications

References 70 publications

Dual RNA-seq of pathogen and host

Dual RNA-seq of pathogen and host

MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

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