The Identification of Circulating MiRNA in Bovine Serum and Their Potential as Novel Biomarkers of Early Mycobacterium avium subsp paratuberculosis Infection

Farrell, DJ; Shaughnessy, Ronan G.; Britton, Louise; MacHugh, David E.; Markey, Bryan; Gordon, Stephen V.

doi:10.1371/journal.pone.0134310

Cited by 52 publications

(69 citation statements)

References 67 publications

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“…Despite extensive evidence in humans, the potential utility of circulating miRNAs as tissue biomarkers in livestock has not been explored widely, with a handful of recent studies identifying potential biomarkers of metabolic status and infection in chicken, pig and cow [20–22]. We recently reported for the first time changes in circulating miRNA levels during early pregnancy (Days 16 and 24) in cattle [23].…”

Section: Introductionmentioning

confidence: 99%

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

Ioannidis

Donadeu

2017

PLoS ONE

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Poor reproductive performance remains a major issue in the dairy industry, with low conception rates having a significant impact on milk production through extended calving intervals. A major limiting factor is the lack of reliable methods for early pregnancy diagnosis. Identification of animals within a herd that fail to conceive within 3 weeks after insemination would allow early re-insemination and shorten calving intervals. In a previous study, we found an increase in plasma miR-26a levels in Day 16-pregnant relative to non-pregnant heifers, however changes in miRNA levels that early during pregnancy were very small which likely prevented the identification of robust biomarkers. In this study, we extended our analyses to a wider interval during pregnancy (Days 8 to 60, n = 11 heifers) with the rationale that this may facilitate the identification of additional early pregnancy miRNA biomarkers. Using small RNA sequencing we identified a total of 77 miRNAs that were differentially expressed on Day 60 relative to Day 0 of pregnancy. We selected 14 miRNAs for validation by RT-qPCR and confirmed significant differences in the expression of let-7f, let-7c, miR-30c, miR-101, miR-26a, miR-205 and miR-143 between Days 0 and 60. RT-qPCR profiling throughout Days 0, 8, 16 and 60 of pregnancy showed a distinct increase in circulating levels of miR-26a (3.1-fold, P = 0.046) as early as Day 8 of pregnancy. In summary, in contrast to earlier stages of pregnancy (≤ Day 24), marked differences in the levels of multiple miRNAs can be detected in circulation by Day 60 in cattle. Retrospective analyses showed miR-26a levels to be increased in circulation as early as Day 8, sooner than previously reported in any species, suggesting a biological role for this miRNA in the very early events of pregnancy.

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Section: Introductionmentioning

confidence: 99%

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

Ioannidis

Donadeu

2017

PLoS ONE

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“…Quantifying miRNA abundance in serum from cattle stratified based on JD presentation (control, mild, moderate, severe) they revealed that a model employing the expression of just 4 miRNA could separate moderate and severely infected animals from the control and mild animals. Conversely, in our previous work using samples from experimental MAP infection models, no significant differential abundance in circulating miRNA could be detected using RNA-seq when comparing uninfected to early stage MAP infection 11 , or from early vs late stage MAP infection 12 .…”

Section: Discussionmentioning

confidence: 61%

“…Previous studies in MAP infected cattle have measured miRNA expression in serum 8 , whole blood 9 and ileal tissues 10 . We have previously investigated circulating miRNA expression in peripheral blood at silent and subclinical MAP infection stages but detected minimal changes that did not provide diagnostic benefit 11,12 . It may, however, be more rewarding to investigate extracellular miRNAs at a local level, with faeces providing a route to explore miRNA species and abundance in the context of the intestinal immune response.…”

Section: Extracellular Micrornas (Mirnas) Are Detectable In the Peripmentioning

confidence: 99%

Identification of microRNAs in bovine faeces and their potential as biomarkers of Johne’s Disease

Shaughnessy

Farrell

Stojkovic

et al. 2020

Sci Rep

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Extracellular microRNAs (miRNAs) are detectable in the peripheral blood and have been touted as potential biomarkers for a range of maladies. The presence and biomarker potential of miRNAs in other biofluids has been less thoroughly explored, particularly in the veterinary realm. Faecal miRNAs are a case in point; while they have been identified largely in rodents and humans, they have not been reported in cattle but may have prognostic or diagnostic value for Johne’s Disease (JD) in cattle, a chronic granulomatous inflammation of the ileum caused by Mycobacterium avium subspecies paratuberculosis (MAP). The aim of this study was thus to characterise the bovine faecal miRNome and to determine the utility of these transcripts as biomarkers for JD. Real-time PCR arrays consisting of 752 miRNA targets, optimised for detection of human miRNA, were used to screen RNA purified from faecal samples obtained from confirmed JD clinical cases vs. healthy controls. Two hundred and fifty-eight miRNAs were detected in bovine faeces, three of which are potentially novel orthologs of known human miRNAs. Differential abundance of three miRNA was evident in animals with clinical JD as compared to healthy controls. Our study has therefore identified a variety of miRNAs in bovine faeces and has demonstrated their utility in differentiating healthy animals from those with late-stage JD, providing potential biomarkers for MAP infection and disease progression.

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“…Recent studies on profiling of miRNAs during clinical and subclinical infection of MAP gave a new perspective to MAP control via miRNA techniques. These studies shown that circulating miRNAs in MAP infected animals retain their integrity under longterm suboptimal storage temperatures and are considered as potential biomarkers [164, 165] that can be exploited for devising the future paratuberculosis control strategies. Apart from miRNAs several compounds such as AS101, SD169 and niclosamide can be used to target IL-10 mediated anti-inflammatory activity.…”

Section: Resultsmentioning

confidence: 99%

The role of IL-10 in Mycobacterium avium subsp. paratuberculosis infection

et al. 2016

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Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen and is the causative agent of Johne’s disease of domestic and wild ruminants. Johne’s disease is characterized by chronic granulomatous enteritis leading to substantial economic losses to the livestock sector across the world. MAP persistently survives in phagocytic cells, most commonly in macrophages by disrupting its early antibacterial activity. MAP triggers several signaling pathways after attachment to pathogen recognition receptors (PRRs) of phagocytic cells. MAP adopts a survival strategy to escape the host defence mechanisms via the activation of mitogen-activated protein kinase (MAPK) pathway. The signaling mechanism initiated through toll like receptor 2 (TLR2) activates MAPK-p38 results in up-regulation of interleukin-10 (IL-10), and subsequent repression of inflammatory cytokines. The anti-inflammatory response of IL-10 is mediated through membrane-bound IL-10 receptors, leading to trans-phosphorylation and activation of Janus Kinase (JAK) family receptor-associated tyrosine kinases (TyKs), that promotes the activation of latent transcription factors, signal transducer and activators of transcription 3 (STAT3). IL-10 is an important inhibitory cytokine playing its role in blocking phagosome maturation and apoptosis. In the current review, we describe the importance of IL-10 in early phases of the MAP infection and regulatory mechanisms of the IL-10 dependent pathways in paratuberculosis. We also highlight the strategies to target IL-10, MAPK and STAT3 in other infections caused by intracellular pathogens.

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The Identification of Circulating MiRNA in Bovine Serum and Their Potential as Novel Biomarkers of Early Mycobacterium avium subsp paratuberculosis Infection

Cited by 52 publications

References 67 publications

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

Identification of microRNAs in bovine faeces and their potential as biomarkers of Johne’s Disease

The role of IL-10 in Mycobacterium avium subsp. paratuberculosis infection

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