Figure - available from: Frontiers in Immunology
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CSF-enriched Macro_C01 cells are highly activated. (A) Heatmaps showing the expression of 22 curated gene signatures (see Supplementary Table 8 ) in myeloid cell clusters. (B) Volcano plot showing differentially expressed genes in CSF Macro_C01 versus other myeloid cells (n = 6). Each red dot indicates passage of the P-value (val) and the fold difference (P < 0.01; average fold-change >1.5). (C) Enrichment of GO bioprocesses (BP) in Macro_C01 cells between CSF cells and PBMCs (options shown; adjusted p-values are indicated by colored bars). (D) Pearson’s correlation regression plot between the Macro_C01 cells complement activation and neuroinflammatory response enrichment score (log2 transformed). Each point represents a unique cell. The Pearson’s test showed R2 > 0.6 as significant. (E) The levels of C1Q, CRP, TNF-α and IL-6 in paired Blood plasma and CSF cells from TBM patients, detected by enzyme-linked immunosorbent assay (ELISA) (n = 8). Paired sample differences were analyzed using by paired t-test; *, P < 0.05; **, P < 0.01; ***, P < 0.001. (F) Monocle2 analysis of myeloid cell cluster pseudotimes: associated cell types and corresponding states (PBMCs, n = 6; CSF, n = 5) are shown.
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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 isolate...
Citations
... The pathogenesis of this meningitis involves complex immune dysregulation, yet the precise immune mechanisms remain poorly understood. scRNA-seq was performed on PBMCs and CSF cells isolated from six children with tuberculous meningitis and discovered that complement-activated microglia-like cells are associated with a neuroinflammatory response that leads to persistent meningitis (129). Consistently, increased levels of complement protein (C1Q), inflammatory markers (C-reactive protein), and inflammatory factors (TNF-a and IL-6) were observed in CSF cells but not in blood. ...
In this comprehensive review, we delve into the significant body of research on single-cell transcriptomics in cerebrospinal fluid (CSF) to understand neurological diseases with autoimmune, neurodegenerative, infectious, or oncogenic origins. We thoroughly examine all published studies in these areas, with a particular focus on multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. For these diseases, we review findings related to immune cells that infiltrate the brain, based on postmortem brain tissue analyses and include CSF cytometry findings. Single-cell RNA sequencing (scRNA-seq), single-cell T cell receptor sequencing (scTCR-seq), and single-cell B cell receptor sequencing (scBCR-seq) are increasingly vital tools for studying CSF to understand various aspects of neurological diseases. These advanced techniques allow researchers to explore the etiopathogenesis of these conditions by identifying the roles and interactions of different immune cells. scRNA-seq provides detailed insights into the gene expression profiles of individual cells, revealing how specific cell types contribute to disease progression. scTCR-seq and scBCR-seq enable the study of clonal expansion in T and B cells, respectively, and facilitate antigen prediction, helping to uncover the nature of antigens that trigger adaptive immune responses. By integrating these technologies, scientists can define new therapeutic targets and categorize patients, leading to more personalized and effective treatments. This review highlights the promising advancements and addresses the current limitations of single-cell transcriptomics in the context of CSF and neurological diseases, setting the stage for future breakthroughs.
... Single-cell ribonucleic acid sequencing data on lumbar CSF of pediatric patients with tuberculous meningitis showed enrichment of highly activated microgliallike cells and other lymphocyte subpopulations (CD4 and CD8 T cells, plasma B cells). Furthermore, these microglial-like cells exhibited complement activation, expressed proinflammatory genes, and were shown to interact mostly with tissue-resident CD4 T cells [25]. ...
Tuberculous meningitis remains the most lethal form of tuberculosis. Despite significant physiological differences adults and children with tuberculous meningitis receive similar treatment and are often grouped together in research. Consequently, differences in tuberculous meningitis characteristics across the lifespan are poorly understood but may be relevant to developing more effective and age-appropriate interventions. In this review we discuss potential age-specific considerations in pathogenesis and pathophysiology, and review literature over the last 5 years to describe clinical characteristics, management, and outcomes across age groups. Children aged <5 years are vulnerable to tuberculosis disease and dissemination due to an immature immune system and the developing brain is highly susceptible to injury associated with neuroinflammation, leading to a greater likelihood of disability that has lifelong impact. Amongst adults, those with human immunodeficiency virus and older people are at greatest risk of death, but more research into the frequency of neurocognitive disability is needed.
... Targeting Macro_C01 activation has been suggested as a therapeutic approach for pediatric TBM. Elevated C1Q, CRP, and cytokines (TNF-a, IL-6) in CSF further indicate their potential as TBM diagnostic biomarkers (115). ...
Tuberculous meningitis (TBM), a severe form of non-purulent meningitis caused by Mycobacterium tuberculosis (Mtb), is the most critical extrapulmonary tuberculosis (TB) manifestation, with a 30–40% mortality rate despite available treatment. The absence of distinctive clinical symptoms and effective diagnostic tools complicates early detection. Recent advancements in nucleic acid detection, genomics, metabolomics, and proteomics have led to novel diagnostic approaches, improving sensitivity and specificity. This review focuses on nucleic acid-based methods, including Xpert Ultra, metagenomic next-generation sequencing (mNGS), and single-cell sequencing of whole brain Tissue, alongside the diagnostic potential of metabolomic and proteomic biomarkers. By evaluating the technical features, diagnostic accuracy, and clinical applicability, this review aims to inform the optimization of TBM diagnostic strategies and explores the integration and clinical translation of multi-omics technologies.
