Systemic immune dysregulation in severe tuberculosis patients revealed by a single-cell transcriptome atlas

Wang, Yi; Sun, Qizhen; Zhang, Yun; Li, Xuelian; Liang, Qingfeng; Guo, Ru; Zhang, Liqun; Xiao, Han; Wang, Jing; Shao, Lingling; Xue, Yu; Yang, Yang; Li, Hua; Nie, Lihui; Shi, Wenhui; Liu, Qiuyue; Zhang, Jing; Duan, Hongfei; Huang, Hairong; Luu, Laurence Don Wai; Tai, Jun; Yang, Xinting; Wang, Guirong

doi:10.1016/j.jinf.2023.03.020

Cited by 23 publications

(24 citation statements)

References 56 publications

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“…Thus, PD-1 regulates the immune response to TB and its inhibition can cause excessive TNF secretion, thereby contributing to TB pathology and accelerated Mtb growth ( 86 ). A single-cell RNA transcriptome study in which data from the healthy control and active TB patients with diverse severity were used that showed that patients with severe disease had elevated numbers of inflammatory immune cells and fewer lymphocytes; they exhibited immune exhaustion and the activation of TNF-induced apoptosis, as well as high cytotoxicity in T helper 1, CD8 + T, and NK cells ( 87 ). These findings shed light on the dysregulated expression of TNF and its roles in TB immunopathogenesis and clinical severity, which will aid the design of novel effective therapies against severe TB.…”

Section: Detrimental Effects Of Tnf During Mycobacterial Infectionmentioning

confidence: 99%

TNF in Human Tuberculosis: A Double-Edged Sword

Yuk,

Kim,

Kim

et al. 2024

Immune Netw

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TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

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Section: Detrimental Effects Of Tnf During Mycobacterial Infectionmentioning

confidence: 99%

TNF in Human Tuberculosis: A Double-Edged Sword

Yuk,

Kim,

Kim

et al. 2024

Immune Netw

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“…Next, the data went through principal component analysis to generate a matrix with 50 principle principal component analysis components as described before. 18 The Python package harmonypy was then used for batch correction. 19 The sample was set as a technical covariate for correction, and parameter θ was set as 2.5.…”

Section: Batch Effect Correction and Cell Clusteringmentioning

confidence: 99%

“…To assess the associations of the state of KD with the compositional changes of the cell cluster, we used the 1-way ANOVA on cell type proportions based on different patient groups. 18,21…”

Section: Anovamentioning

confidence: 99%

“…Subsequently, we investigated the potential sources of cytokine production in KD. Based on the expression of proinflammatory response genes and cytokine genes that have been reported previously (Table S8), 18,21 we initially established an inflammatory and cytokine score for each cell subset. We then utilized these 2 correlated scores as indicators to evaluate the potential contribution of each subset to the inflammatory cytokine storm.…”

Section: Inflammatory Cytokine Storm May Be a Crucial Driver For Cal ...mentioning

confidence: 99%

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Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

Chen,

Yang,

Zhang

et al. 2024

ATVB

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BACKGROUND: Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear. METHODS: Here, we conducted single-cell transcriptome analyses of 212 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls. RESULTS: KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4 + T, CD8 + T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B, CXCL16, TNFSF10, and IL1RN, mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD. CONCLUSIONS: Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.

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“…During the infection process, innate immunity and adaptive immunity play distinct roles in the defense and elimination of M.tb [3] . While adaptive immunity, mediated by T lymphocytes, is the determined factor of the outcome and TB severity [4] . CD4 T cells and CD8 T cells are the two major components of T lymphocytes, there is su cient evidence supporting that CD4 T cells release cytokines, such as interferonγ (IFN-γ) in response to M.tb speci c antigens to enhance the phagocytosis of macrophage [5][6][7] to control TB, mice, and macaques with depleted CD4 T cells or humans with de cient CD4 T cells, particularly those with HIV, are dramatically susceptible to reinfection of TB or progress into active TB from LTBI [8] .…”

Section: Introductionmentioning

confidence: 99%

CD8 T cell count was not associated with the severity of pulmonary tuberculosis

Xiang

Liu

et al. 2023

Preprint

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Purposes: Tuberculosis is still a global health threat, among those, severe pulmonary tuberculosis causes significant mortality. CD8 T cell plays an important role in the pathogenesis of tuberculosis. However, the association between CD8 T cell count and the severity of pulmonary TB (PTB) has not been evaluated. Methods: Patients admitted to a tertiary hospital from January 2013 to December 2017 and diagnosed as PTB with T cell subtypes tested were screened for recruitment. We compared the demographics and clinical manifestations between severe PTB patients and non-severe PTB patients, then analyzed the independent risk factors related to severe PTB after adjusting covariates. Results: There were 279 patients enrolled for analysis, 180 were severe PTB (64.5%) and 99 were non-severe PTB (35.5%). Through univariate and multivariate analysis, lung cavity (aOR 4.631, 95% CI [1.798-12.853], P= 0.002) and albumin (aOR 0.952,95% CI [0.905-1.000], P=0.05) were associated severe PTB. While CD4 T cell count (aOR 1.00,95% CI [0.999-1.001], P=0.794), CD8 T cell count (aOR 1.00,95% CI [0.999-1.001], P=0.973), and lymphocyte (aOR 0.82,95% CI [0.389-1.774], P=0.603) were not associated with severe PTB. Conclusions: Lung cavity and lower albumin level were related with an increased risk of severe PTB, while CD4, CD8 T cells count and lymphocytes were not with the severity of PTB. May be not the count, but the function of T cells plays a crucial role in the pathogenesis of tuberculosis.

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Systemic immune dysregulation in severe tuberculosis patients revealed by a single-cell transcriptome atlas

Cited by 23 publications

References 56 publications

TNF in Human Tuberculosis: A Double-Edged Sword

TNF in Human Tuberculosis: A Double-Edged Sword

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

CD8 T cell count was not associated with the severity of pulmonary tuberculosis

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