Mycobacterium tuberculosis infection drives a Type I IFN signature in lung lymphocytes. Mycobacterium tuberculosis infection drives a Type I IFN signature in lung lymphocytes

Mycobacterium tuberculosis (Mtb) infects a quarter of the world’s population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at cellular level is crucial to design better strategies to control TB. We have employed single-cell RNA-seq approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show enrichment of type I IFN responsive phenotypes among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We have identified Ly6A as a novel lymphoid cell activation marker and validated its upregulation in activated lymphoid cells post Mtb infection. The cross analysis of type I IFN signature in human TB infected peripheral blood samples further validates our results. These findings significantly contribute toward understanding and characterizing the transcriptional parameters at single-cell depth in a highly relevant and reproducible mouse model of TB. Overall design: To characterize the lung lymphocyte landscape of mice infected with low dose Mtb, we performed 10x scRNA-seq on single-cells from the lungs of control (uninfected, n = 2), 50 days post-infection (dpi) (D50 Inf, n = 3), and 100 dpi (D100 Inf, n = 3) mice

结核分枝杆菌（Mycobacterium tuberculosis, Mtb）感染全球四分之一人口，引发结核病（tuberculosis, TB），是全球主要致死病因之一。清晰解析细胞层面免疫应答的动态变化，对于设计更有效的结核病防控策略至关重要。本研究针对健康小鼠与结核分枝杆菌感染小鼠的肺淋巴细胞，采用单细胞RNA测序（single-cell RNA-seq）技术开展分析。研究结果表明，结核分枝杆菌感染小鼠肺部的淋巴样细胞簇中，I型干扰素应答表型显著富集；同时自然杀伤（NK）细胞呈现热休克应答特征。本研究鉴定出Ly6A作为新型淋巴样细胞活化标志物，并验证了结核分枝杆菌感染后活化淋巴样细胞中该分子的表达上调。对人类结核病感染者外周血样本中的I型干扰素特征开展交叉分析，进一步验证了本研究的结论。上述发现为在高度相关且可重复的结核病小鼠模型中，以单细胞分辨率解析转录调控特征提供了重要支撑。整体实验设计：为表征低剂量结核分枝杆菌感染小鼠的肺淋巴细胞图谱，本研究对对照组（未感染，n=2）、感染后50天（dpi，D50 Inf，n=3）及感染后100天（dpi，D100 Inf，n=3）小鼠的肺部单细胞进行了10x scRNA-seq测序。