Yunnan Province Key Laboratory of Children's Major Diseases Research, Department of Pathogen Biology and Immunology, School of Basic Medicine, Kunming Medical University, Kunming 650500, China.
Yunnan Provincial Key Laboratory of Public Health and Biosafety, School of Public Health, Kunming Medical University, Kunming 650500, China.
Int J Mol Sci. 2024 Sep 16;25(18):9971. doi: 10.3390/ijms25189971.
Observational studies indicate that variations in peripheral blood mononuclear cell (PBMC) subsets are associated with an increased risk of pulmonary tuberculosis (PTB) and coronavirus disease 2019 (COVID-19), but causal validation is lacking. Here, we combined single-cell expression quantitative trait locus (sc-eQTL) and two-sample mendelian randomization (MR) analyses to elucidate the causal relationship between PBMC subsets and the occurrence of PTB and COVID-19 and verified by RT-qPCR. We observed an increase in the CD4 Effective Memory T Cell (CD4 T) cluster in both PTB and COVID-19 patients according to the single-cell transcriptional landscape of PBMC. Through MR analysis using an inverse variance weighted (IVW) method, we found strong evidence of positive correlations between CD4 T cell markers (GBP2, TRAV1-2, and ODF2L) and PTB, and between markers (LAG3 and SLFN5) and COVID-19, especially highlighted by lead eQTL-SNPs of GBP2 (rs2256752, = 4.76321 × 10) and LAG3 (rs67706382, = 6.16× 10). Similar results were observed in validation sets, and no pleiotropy was detected in sensitivity analyses including weighted median (WM), MR-Egger, MR-pleiotropy residual sum and outlier, and leave-one-out analyses (all > 0.05). We visualized the colocalization of marker-eQTLs and markers of PTB and COVID-19 genome-wide association study (GWAS) associations. Based on CellChat analyses, monocytes communicated predominantly with CD4 T cells positively expressing PTB markers (GBP2, TRAV1-2, and ODF2L) and COVID-19 markers (LAG3 and SLFN5) in both PTB and COVID-19. Our data suggest a causal effect between two key CD4 T cell markers (GBP2 and LAG3) and the risk for PTB and COVID-19 infection. Our findings provide novel insights into the biological mechanism for PTB and COVID-19 infection, but future single-cell studies are necessary to further enhance understanding of this find.
观察性研究表明，外周血单个核细胞（PBMC）亚群的变化与肺结核（PTB）和 2019 年冠状病毒病（COVID-19）的风险增加有关，但因果关系尚未得到验证。在这里，我们结合单细胞表达数量性状基因座（sc-eQTL）和两样本孟德尔随机化（MR）分析，阐明 PBMC 亚群与 PTB 和 COVID-19 发生的因果关系，并通过 RT-qPCR 进行验证。我们根据 PBMC 的单细胞转录图谱观察到 PTB 和 COVID-19 患者的 CD4 有效记忆 T 细胞（CD4 T）簇增加。通过使用逆方差加权（IVW）方法的 MR 分析，我们发现 CD4 T 细胞标志物（GBP2、TRAV1-2 和 ODF2L）与 PTB 之间以及标志物（LAG3 和 SLFN5）与 COVID-19 之间存在正相关的有力证据，其中 GBP2（rs2256752， = 4.76321 × 10）和 LAG3（rs67706382， = 6.16× 10）的主要 eQTL-SNPs 尤为突出。在验证集中观察到了类似的结果，并且在包括加权中位数（WM）、MR-Egger、MR-多效性残差和异常值以及单样本分析（所有 > 0.05）在内的敏感性分析中未检测到多效性。我们可视化了标记物-eQTLs 与 PTB 和 COVID-19 全基因组关联研究（GWAS）关联的标记物的共定位。基于 CellChat 分析，在 PTB 和 COVID-19 中，单核细胞主要与阳性表达 PTB 标志物（GBP2、TRAV1-2 和 ODF2L）和 COVID-19 标志物（LAG3 和 SLFN5）的 CD4 T 细胞进行通讯。我们的数据表明，两个关键的 CD4 T 细胞标志物（GBP2 和 LAG3）与 PTB 和 COVID-19 感染风险之间存在因果关系。我们的研究结果为 PTB 和 COVID-19 感染的生物学机制提供了新的见解，但需要进一步的单细胞研究来进一步增强对这一发现的理解。
