TMEM176B的功能评估及其在严重呼吸道病毒感染中的预测作用：单细胞与全转录组RNA测序的整合分析

Functional evaluation of TMEM176B and its predictive role for severe respiratory viral infection through integrated analysis of single-cell and bulk RNA-sequencing

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JOURNAL OF MEDICAL VIROLOGY

影响因子:4.6

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,

DOI: 10.1002/jmv.29954

摘要

跨膜蛋白TMEM176B主要定位于内体膜，被报道为恶性疾病中的免疫调节因子。然而，其在呼吸道病毒感染中的生物学功能尚未明确。为研究该基因的功能及预后价值，本文从Gene Expression Omnibus数据库筛选了六个基因集进行研究。首先，评估了TMEM176B及其共表达基因在不同水平（细胞、外周血、肺组织）上的功能。随后，利用机器学习算法分析了TMEM176B及其互作基因与预后的关系。在重要性评估和变量筛选后，建立了预后模型，并通过外部数据集验证其可靠性。体外实验验证了TMEM176B的功能。结果显示，TMEM176B及其共表达基因参与炎症体激活、髓系免疫细胞发育及免疫细胞浸润等多项过程。机器学习筛选出27个包括TMEM176B的互作基因模块，用于预测严重呼吸道病毒感染的预后，其在模型中的ROC曲线下面积（AUC）分别为0.986和0.905。进一步通过体外实验确认，在TMEM176B敲除的THP-1来源巨噬细胞中，病毒载量、NLRP3激活及细胞死亡显著增强。本研究揭示TMEM176B在呼吸道病毒感染中的多项生物学功能及其潜在预后价值，有望为重症呼吸道病毒感染的临床管理提供新见解。

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.