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Single-Cell Sequencing Reveals Functional Alterations in Tuberculosis.

ABSTRACT: Despite its importance, the functional heterogeneity surrounding the dynamics of interactions between mycobacterium tuberculosis and human immune cells in determining host immune strength and tuberculosis (TB) outcomes, remains far from understood. This work now describes the development of a new technological platform to elucidate the immune function differences in individuals with TB, integrating single-cell RNA sequencing and cell surface antibody sequencing to provide both genomic and phenotypic information from the same samples. Single-cell analysis of 23 990 peripheral blood mononuclear cells from a new cohort of primary TB patients and healthy controls enables to not only show four distinct immune phenotypes (TB, myeloid, and natural killer (NK) cells), but also determine the dynamic changes in cell population abundance, gene expression, developmental trajectory, transcriptomic regulation, and cell-cell signaling. In doing so, TB-related changes in immune cell functions demonstrate that the immune response is mediated through host T cells, myeloid cells, and NK cells, with TB patients showing decreased naive, cytotoxicity, and memory functions of T cells, rather than their immunoregulatory function. The platform also has the potential to identify new targets for immunotherapeutic treatment strategies to restore T cells from dysfunctional or exhausted states.

SUBMITTER: Lyu M

PROVIDER: S-EPMC10953544 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Single-Cell Sequencing Reveals Functional Alterations in Tuberculosis.

Lyu Mengyuan M Xu Gaolian G Zhou Jian J Reboud Julien J Wang Yili Y Lai Hongli H Chen Yi Y Zhou Yanbing Y Zhu Guiying G Cooper Jonathan M JM Ying Binwu B

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240108 11

Despite its importance, the functional heterogeneity surrounding the dynamics of interactions between mycobacterium tuberculosis and human immune cells in determining host immune strength and tuberculosis (TB) outcomes, remains far from understood. This work now describes the development of a new technological platform to elucidate the immune function differences in individuals with TB, integrating single-cell RNA sequencing and cell surface antibody sequencing to provide both genomic and phenot ...[more]

PMID: 38192178

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Project description:Objective: Osteoarthritis (OA) is a common joint disorder characterized by degenerative articular cartilage, subchondral bone remodeling, and inflammation. Increasing evidence suggests that the substantial crosstalk between cartilage and synovium is closely related to Osteoarthritis development, but the events that cause this degeneration remain unknown. This study aimed to explore the alterations in intercellular communication involved in the pathogenesis of Osteoarthritis using bioinformatics analysis. Methods: Single-cell transcriptome sequencing (scRNA-seq) profiles derived from articular cartilage tissue of patients with Osteoarthritis were downloaded from a public database. Chondrocyte heterogeneity was assessed using computational analysis, and cell type identification and clustering analysis were performed using the "FindClusters" function in the Seurat package. Intercellular communication networks, including major signaling inputs and outputs for cells, were predicted, and analyzed using CellChat. Results: Seven molecularly defined chondrocytes clusters (homeostatic chondrocytes, hypertrophic chondrocyte (HTC), pre-HTC, regulatory chondrocytes, fibro-chondrocytes (FC), pre-FC, and reparative chondrocyte) with different compositions were identified in the damaged cartilage. Compared to those in the intact cartilage, the overall cell-cell communication frequency and communication strength were remarkably increased in the damaged cartilage. The cellular communication among chondrocyte subtypes mediated by signaling pathways, such as PTN, VISFATIN, SPP1, and TGF-β, was selectively altered in Osteoarthritis. Moreover, we verified that SPP1 pathway enrichment scores increased, but VISFATIN pathway enrichment scores decreased based on the bulk rna-seq datasets in Osteoarthritis. Conclusion: Our results revealed alterations in cell-cell communication among OA-related chondrocyte subtypes that were mediated by specific signaling pathways, which might be a crucial underlying mechanism associated with Osteoarthritis progression.

Project description:BackgroundEpigenetic abnormalities caused by superovulation have recently attracted increasing attention. Superovulation with exogenous hormones may prevent oocytes from establishing an appropriate epigenetic state, and this effect may extend to the methylation programming in preimplantation embryos, as de novo DNA methylation is a function of developmental stage of follicles and oocyte size. Follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG) are common gonadotropins used for superovulation, and appropriate concentrations of these gonadotropins might be necessary. However, no systematic study on the effects of DNA methylation alterations in oocytes associated with superovulation with different dosages of FSH/hMG at the single-cell level has yet been reported. In the current study, different dosages of FSH/hMG combined with human chorionic gonadotropin (hCG) were used in female mice to generate experimental groups, while naturally matured oocytes and oocytes superovulated with only hCG were respectively used as controls. Single-cell level DNA methylation sequencing was carried out on all these matured oocytes.ResultsIn this study, we revealed that the genome-wide methylation pattern and CG methylation level of the maternal imprinting control regions of all mature oocytes were globally conserved and stable. However, methylation alterations associated with superovulation were found at a specific set of loci, and the differentially methylated regions (DMRs) mainly occurred in regions other than promoters. Furthermore, some of the annotated genes in the DMRs were involved in biological processes such as glucose metabolism, nervous system development, cell cycle, cell proliferation, and embryo implantation and were altered in all dosages of FSH/hMG group (for example, Gfod2 and SYF2). Other genes were impaired only after high gonadotropin dosages (for instance, Sox17 and Phactr4).ConclusionsIn conclusion, the current study addressed the effects of superovulation on DNA methylation from the perspective of different dosages of gonadotropins at the single-cell level. We found that the genome-wide DNA methylation landscape was globally preserved irrespective of superovulation or of the kind and dosage of gonadotropins used, whereas the methylation alterations associated with superovulation occurred at a specific set of loci. These observed effects reflect that superovulation recruits oocytes that would not normally be ovulated or that have not undergone complete epigenetic maturation. Our results provide an important reference for the safety assessment of superovulation with different dosages of gonadotropins. However, it should be noted that this study has some limitations, as the sample number and library coverage of analyzed oocytes were relatively low. Future studies with larger sample sizes and high-coverage libraries that examine the effects of superovulation on embryo development and offspring health as well as the underlying mechanisms are still needed.

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Single-Cell Sequencing Reveals Functional Alterations in Tuberculosis.

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Single-Cell Sequencing Reveals Functional Alterations in Tuberculosis.

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