TMEM176B的功能评估及其对严重呼吸病毒感染的预测作用，通过对单细胞和大量RNA序列的综合分析
Functional evaluation of TMEM176B and its predictive role for severe respiratory viral infection through integrated analysis of single-cell and bulk RNA-sequencing
影响因子:4.60000
分区:医学3区 / 病毒学3区
发表日期:2024 Oct
作者:
Congcong Shang, Jiapei Yu, Shumei Zou, Hui Li, Bin Cao,
摘要
跨膜蛋白176b（TMEM176B）主要局部位于内体膜上，据报道是恶性疾病的免疫调节因素。但是，该分子的生物学功能在呼吸道病毒感染过程中仍未确定。为了研究该基因的功能和预后价值，从基因表达综合数据库中选择了六个基因集以进行研究。首先，在不同水平（细胞，外周血，肺组织）评估TMEM176B及其共表达基因的功能。之后，使用一种机器学习算法来分析TMEM176B与其相互作用基因与预后之间的关系。在重要性评估和可变筛选之后，建立了预后模型。最后，通过外部数据集进一步验证了模型的可靠性。进行了体外实验以验证TMEM176B的功能。 TMEM176B及其共表达的基因参与多种过程，例如炎性体激活，髓样免疫细胞发育和免疫细胞浸润。机器学习进一步筛选了27个相互作用的基因模块，包括TMEM176B作为严重呼吸病毒感染的预后模型，在ROC曲线（AUC）下的区域分别为0.986和0.905，在衍生和外部验证集中分别为0.905。我们进一步证实，通过体外实验，TMEM176B - / - THP-1划分的巨噬细胞在TMEM176B - / - THP-1划分的巨噬细胞中显着增强了病毒载量以及NLRP3激活和细胞死亡。我们的研究表明，TMEM176B参与了呼吸病毒感染中广泛的生物学功能，并且具有潜在的预后价值，这有望为严重呼吸道病毒感染宿主的临床管理带来新的见解。
Abstract
Transmembrane protein 176B (TMEM176B), localized mainly on the endosomal membrane, has been reported as an immune regulatory factor in malignant diseases. However, the biological function of this molecule remains undetermined during respiratory viral infections. To investigate the functions and prognostic value of this gene, six gene sets were selected from the Gene Expression Omnibus database for research. First, the function of TMEM176B and its co-expressed genes were evaluated at different levels (cell, peripheral blood, lung tissue). Afterwards, a machine learning algorithm was utilized to analyze the relationship between TMEM176B and its interacting genes with prognosis. After importance evaluation and variable screening, a prognostic model was established. Finally, the reliability of the model was further verified through external data sets. In vitro experiments were conducted to validate the function of TMEM176B. TMEM176B and its co-expressed genes are involved in multiple processes such as inflammasome activation, myeloid immune cell development, and immune cell infiltration. Machine learning further screened 27 interacting gene modules including TMEM176B as prognostic models for severe respiratory viral infections, with the area under the ROC curve (AUCs) of 0.986 and 0.905 in derivation and external validation sets, respectively. We further confirmed that viral load as well as NLRP3 activation and cell death were significantly enhanced in TMEM176B-/- THP-1-differentiated macrophages via in vitro experiments. Our study revealed that TMEM176B is involved in a wide range of biological functions in respiratory viral infections and has potential prognostic value, which is expected to bring new insights into the clinical management of severe respiratory viral infection hosts.