Keewan Esra'a, Naser Saleh A
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra drive, Orlando, FL 32816 USA.
Gut Pathog. 2020 Oct 15;12:48. doi: 10.1186/s13099-020-00387-0. eCollection 2020.
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 (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.
We determined the incidence of miR-146a in 42 blood samples from clinical CD patients and controls. We also measured the effect of 4 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.
MiR-146a was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) 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 (67%) compared to samples with normal genotype (33%).
The data clearly associates miR-146a 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.
微小RNA-146a（miR-146a）作为一种效应介质，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Notch-1信号在感染期间巨噬细胞极化和反应中起关键作用。我们采用克罗恩病（CD）中的胞内分枝杆菌（MAP）感染作为模型，以证明Notch-1/白细胞介素-6（IL-6）信号对基于髓细胞白血病序列1（MCL-1）的细胞凋亡以及细胞内MAP感染和持续存在的作用。本研究旨在调查miR146a基因多态性对我们的MAP-CD模型中免疫反应和感染的影响。
我们测定了42份来自临床CD患者和对照的血样中miR-146a的发生率。我们还在研究组中测量了4对Notch-1和IL-6表达以及血浆IL-6蛋白水平的影响。最后，我们分析血样中的MAP DNA，并研究其与miR-146a多态性的任何相关性。使用不成对双尾t检验、不成对双尾z分数和优势比分析样本的统计学意义。P < 0.05被认为具有显著性。
与健康对照（21.7%）相比，CD患者中miR-146a的检出率更高（52.6%）。杂合子多态性分别使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（9%）相比，CD样本中检测到的MAP感染更多（63%）。令人惊讶的是，与正常基因型样本（33%）相比，具有[具体基因型]的样本中MAP感染的检出率更高（67%）。
数据清楚地表明miR-146a与过度活跃的免疫反应相关，并增加了感染风险。在我们努力了解对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的易感性和冠状病毒病（COVID-19）的发展过程中，这项研究现在更具相关性。这项研究表明，COVID-19患者之间的基因变异可能预测谁感染、出现症状加重以及可能死亡的风险更高。计划开展一项对来自不同疾病组的更多临床样本的大规模研究。
