Abstract
BackgroundMiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. Recently, we reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. We employed Mycobacterium avium paratuberculosis (MAP) infection in Crohn’s disease (CD) as a model to demonstrate the role of Notch-1/IL-6 signaling on MCL-1 based apoptosis and intracellular MAP infection and persistence. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model.MethodsWe determined the incidence of miR-146a rs2910164 G > C in 42 blood samples from clinical CD patients and controls. We also measured the effect of rs2910164 on expression of Notch-1 and IL-6, and plasma IL-6 protein levels in our study group. Finally, we analyzed the blood samples for MAP DNA and studied any correlation with miR-146a polymorphism. Samples were analyzed for statistical significance using unpaired tow-tailed t-test, unpaired two-tailed z-score and odds ratio. P < 0.05 considered significant.ResultsMiR-146a rs2910164 GC was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) rs2910164 GC Heterozygous polymorphism upregulated Notch-1 and IL-6, by 0.9 and 1.7-fold, respectively. As expected, MAP infection was detected more in CD samples (63%) compared to healthy controls (9%). Surprisingly, MAP infection was detected at a higher rate in samples with rs2910164 GC (67%) compared to samples with normal genotype (33%).ConclusionsThe data clearly associates miR-146a rs2910164 GC with an overactive immune response and increases the risk to acquire infection. The study is even more relevant now in our efforts to understand susceptibility to SARS-CoV-2 infection and the development of COVID-19. This study suggests that genetic variations among COVID-19 patients may predict who is at a higher risk of acquiring infection, developing exacerbating symptoms, and possibly death. A high scale study with more clinical samples from different disease groups is planned.
Highlights
MicroRNAs are a class of small, noncoding RNA (~ 22 nucleotides in length) that post-transcriptionally regulate one-third of protein-coding genes [1]
Various studies reported that rs2910164 GC on the passenger strand of miR-146a precursor has been associated with many pathological conditions including Rheumatoid Arthritis (RA) [13], severe sepsis [14], tuberculosis [15], and cancer[16]
We investigated the possible interaction between Notch-1 and miR-146a polymorphism which may interfere with Notch-1 expression and downstream signaling and susceptibility to Mycobacterium avium paratuberculosis (MAP) infection in Crohn’s disease (CD)
Summary
MicroRNAs (miRNAs) are a class of small, noncoding RNA (~ 22 nucleotides in length) that post-transcriptionally regulate one-third of protein-coding genes [1]. MiRNAs have been described as a novel mediator of the host immune response against infection, mostly through regulating proteins involved in innate and adaptive immune systems [5]. MiR-146a, a member of miRNAs family, encoded on human chromosome 5q33.3, has an essential role in the regulation of immune cell differentiation, inflammatory cytokines production, host defense, and various immunological conditions [6, 7]. Various studies reported that rs2910164 GC (single nucleotide polymorphism) on the passenger strand of miR-146a precursor has been associated with many pathological conditions including Rheumatoid Arthritis (RA) [13], severe sepsis [14], tuberculosis [15], and cancer[16]. MiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. We reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model
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