Background:MiR-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. Methods:We 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. Results:MiR-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%). Conclusions:The 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.

译文

背景:效应子介体MiR-146a靶向Notch-1,并调节先天性和适应性免疫系统反应。最近,我们报道了Notch-1信号在感染过程中在巨噬细胞极化和反应中起关键作用。我们在克罗恩病(CD)中采用鸟分枝杆菌副结核分枝杆菌(MAP)感染作为模型来证明Notch-1 / IL-6信号在基于MCL-1的细胞凋亡以及细胞内MAP感染和持久性中的作用。这项研究旨在调查miR146a多态性对我们MAP-CD模型中免疫反应和感染的影响。
方法:我们确定了42例临床CD患者和对照组血液样本中miR-146a rs2910164 G> C的发生率。我们还测量了rs2910164对Notch-1和IL-6表达以及血浆IL-6蛋白水平的影响。最后,我们分析了血液样本中的MAP DNA,并研究了与miR-146a多态性的任何相关性。使用不成对的拖尾t检验,不成对的两尾z得分和比值比分析样本的统计显着性。 P <0.05被认为是显着的。
结果:与健康对照组(21.7%)相比,检测到MiR-146a rs2910164 GC的CD发生率更高(52.6%)rs2910164 GC杂合多态性分别将Notch-1和IL-6上调0.9倍和1.7倍。正如预期的那样,与健康对照组(9%)相比,在CD样品(63%)中检测到了MAP感染。令人惊讶的是,与具有正常基因型的样本(33%)相比,使用rs2910164 GC的样本(67%)以更高的比率检测到MAP感染。
结论:这些数据清楚地将miR-146a rs2910164 GC与过度活跃的免疫反应相关联,并增加了获得感染的风险。现在,这项研究与我们了解SARS-CoV-2感染的易感性和COVID-19的发展的努力更加相关。这项研究表明,COVID-19患者之间的遗传变异可以预测谁更容易感染,出现恶化症状甚至死亡。计划进行大规模研究,其中包括来自不同疾病组的更多临床样品。

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