Single-cell transcriptome reveals highly complement activated microglia cells in association with pediatric tuberculous meningitis

作者全名：Mo, Siwei; Shi, Chenyan; Cai, Yi; Xu, Maozhu; Xu, Hongmei; Xu, Yuzhong; Zhang, Kehong; Zhang, Yue; Liu, Jiao; Che, Siyi; Liu, Xiangyu; Xing, Chaonan; Long, Xiaoru; Chen, Xinchun; Liu, Enmei

作者地址：[Mo, Siwei; Liu, Xiangyu; Long, Xiaoru; Liu, Enmei] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders,Chongqing, Dept Resp Med,China Int Sci & Technol Cooperat Bas, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China; [Mo, Siwei; Shi, Chenyan; Cai, Yi; Zhang, Yue; Xing, Chaonan; Chen, Xinchun] Shenzhen Univ, Sch Med, Dept Pathogen Biol, Guangdong Prov Key Lab Reg Immun & Dis, Shenzhen, Peoples R China; [Shi, Chenyan] Shenzhen Univ, Med Sch, Sch Publ Hlth, Shenzhen, Guangdong, Peoples R China; [Xu, Maozhu] Maternal & Child Care Hlth Hosp Zunyi City, Zunyi, Guizhou, Peoples R China; [Xu, Hongmei] Chongqing Med Univ, Childrens Hosp, Dept Infect Dis, Chongqing, Peoples R China; [Xu, Yuzhong; Zhang, Kehong] Shenzhen Univ, Shenzhen Baoan Hosp, Affiliated Hosp 2, Dept Clin Lab, Shenzhen, Peoples R China; [Liu, Jiao] Chongqing Med Univ, Childrens Hosp, Pediat Res Inst, Chongqing, Peoples R China; [Che, Siyi] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Radiol,Chongqing Key Lab Pediat, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China

通信作者：Long, XR; Liu, EM (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders,Chongqing, Dept Resp Med,China Int Sci & Technol Cooperat Bas, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China.; Chen, XC (通讯作者)，Shenzhen Univ, Sch Med, Dept Pathogen Biol, Guangdong Prov Key Lab Reg Immun & Dis, Shenzhen, Peoples R China.

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001221051700001

JCR分区：Q1

影响因子：5.7

年份：2024

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：pediatric tuberculous meningitis; cerebrospinal fluid; microglia; inflammation; single Cell RNA sequencing; complement

摘要：Background Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are unclear.Methods We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis.Results We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-alpha and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6.Discussion We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by Mtb-infected tissues.

基金机构：National Key Research and Development Program projects [2022YFC2302900]; Shenzhen Medical Research Special Fund Project [A2304001]; National Natural Science Youth Foundation of China [82202574, 82304839]; General program of clinical Medical Research [NCRCCHD-2020-GP-06]; Chongqing Science and health joint medical scientific research project [2023MSXM051]

基金资助正文：The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key Research and Development Program projects (2022YFC2302900), the Shenzhen Medical Research Special Fund Project (A2304001), National Natural Science Youth Foundation of China (82202574, 82304839), General program of clinical Medical Research (NCRCCHD-2020-GP-06), and Chongqing Science and health joint medical scientific research project (2023MSXM051).