Mast cells promote pathology and susceptibility in tuberculosis
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Curated by eLife
eLife Assessment
In this useful study, the authors use published scRNA-seq data to highlight the importance of mast cells (MCs) in TB granulomas, reporting a comparative assessment of chymase- and tryptase-expressing MCs in the lungs of tuberculosis-infected individuals and non-human primates, with MC-deficient mice showing reduced lung bacterial burden and pathology during infection. Whilst the findings are helpful, the evidence to support conclusions is inconsistent across models and thus incomplete. Specifically, the data supporting a role for MCs in coordinating cytokine responses to modulate pathology, susceptibility to tuberculosis, and dissemination during infection are weak.
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Abstract
Abstract
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects approximately one-fourth of the world’s population. While most infected individuals are asymptomatic, latent TB infection (LTBI) can progress to cause pulmonary TB (PTB). We recently reported an increased accumulation of mast cells (MCs) in lungs of macaques with PTB, compared with LTBI in macaques. MCs respond in vitro to Mtb exposure via degranulation and by inducing proinflammatory cytokines. In the current study, we show the dominant production of chymase by MCs in granulomas of humans and macaques with PTB. Using scRNA seq analysis, we show that MCs found in LTBI and healthy lungs in macaques are enriched in genes involved in tumor necrosis factor alpha, cholesterol and transforming growth factor beta signaling. In contrast, MCs clusters found in PTB express transcriptional signatures associated with interferon gamma, oxidative phosphorylation, and MYC signaling. Additionally, MC deficiency in the mouse model showed improved control of Mtb infection that coincided with reduced accumulation of lung myeloid cells and diminished inflammation at chronic stages. Thus, these collective results provide novel evidence for the pathological contribution of MCs during Mtb infection and may represent a novel target for host directive therapy for TB.
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Author Response:
Reviewer #1 (Public Review):
Summary:
The study by Gupta et al. investigates the role of mast cells (MCs) in tuberculosis (TB) by examining their accumulation in the lungs of M. tuberculosis-infected individuals, non-human primates, and mice. The authors suggest that MCs expressing chymase and tryptase contribute to the pathology of TB and influence bacterial burden, with MC-deficient mice showing reduced lung bacterial load and pathology.
Strengths:
(1) The study addresses an important and novel topic, exploring the potential role of mast cells in TB pathology.
(2) It incorporates data from multiple models, including human, non-human primates, and mice, providing a broad perspective on MC involvement in TB.
(3) The finding that MC-deficient mice exhibit reduced lung bacterial burden is an interesting and potentially …
Author Response:
Reviewer #1 (Public Review):
Summary:
The study by Gupta et al. investigates the role of mast cells (MCs) in tuberculosis (TB) by examining their accumulation in the lungs of M. tuberculosis-infected individuals, non-human primates, and mice. The authors suggest that MCs expressing chymase and tryptase contribute to the pathology of TB and influence bacterial burden, with MC-deficient mice showing reduced lung bacterial load and pathology.
Strengths:
(1) The study addresses an important and novel topic, exploring the potential role of mast cells in TB pathology.
(2) It incorporates data from multiple models, including human, non-human primates, and mice, providing a broad perspective on MC involvement in TB.
(3) The finding that MC-deficient mice exhibit reduced lung bacterial burden is an interesting and potentially significant observation.
Weaknesses:
(1) The evidence is inconsistent across models, leading to divergent conclusions that weaken the overall impact of the study.
The strength of the study is the use of multiple models including mouse, non-human primate as well as human samples. The conclusions have now been refined to reflect the complexity of the disease and the use of multiple models.
(2) Key claims, such as MC-mediated cytokine responses and conversion of MC subtypes in granulomas, are not well-supported by the data presented.
To address the reviewer’s comments, we will carry out further experimentation to strengthen the link between MC subtypes and cytokine responses.
(3) Several figures are either contradictory or lack clarity, and important discrepancies, such as the differences between mouse and human data, are not adequately discussed.
We will further clarify the figures and streamline the discussions between the different models used in the study.
(4) Certain data and conclusions require further clarification or supporting evidence to be fully convincing.
We will either provide clarification or supporting evidence for some of the key conclusions in the paper.
Reviewer #2 (Public review):
Summary:
The submitted manuscript aims to characterize the role of mast cells in TB granuloma. The manuscript reports heterogeneity in mast cell populations present within the granulomas of tuberculosis patients. With the help of previously published scRNAseq data, the authors identify transcriptional signatures associated with distinct subpopulations.
Strengths:
(1) The authors have carried out a sufficient literature review to establish the background and significance of their study.
(2) The manuscript utilizes a mast cell-deficient mouse model, which demonstrates improved lung pathology during Mtb infection, suggesting mast cells as a potential novel target for developing host-directed therapies (HDT) against tuberculosis.
Weaknesses:
(1) The manuscript requires significant improvement, particularly in the clarity of the experimental design, as well as in the interpretation and discussion of the results. Enhanced focus on these areas will provide better coherence and understanding for the readers.
The strength of the study is the use of multiple models including mouse, non-human primate as well as human samples. The conclusions have now been refined to reflect the complexity of the disease and the use of multiple models.
(2) Throughout the manuscript, the authors have mislabelled the legends for WT B6 mice and mast cell-deficient mice. As a result, the discussion and claims made in relation to the data do not align with the corresponding graphs (Figure 1B, 3, 4, and S2). This discrepancy undermines the accuracy of the conclusions drawn from the results.
We apologize for the discrepancy which will be corrected in the revised manuscript
(3) The results discussed in the paper do not add a significant novel aspect to the field of tuberculosis, as the majority of the results discussed in Figure 1-2 are already known and are a re-validation of previous literature.
This is the first study which has used mouse, NHP and human TB samples from Mtb infection to characterize and validate the role of MC in TB. We believe the current study provides significant novel insights into the role of MC in TB.
(4) The claims made in the manuscript are only partially supported by the presented data. Additional extensive experiments are necessary to strengthen the findings and enhance the overall scientific contribution of the work.
We will either provide clarification or supporting evidence for some of the key conclusions in the paper.
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resulted in limiting inflammation
How would degranulation limit inflammation? The MCs are releasing pro-inflammatory cytokines, as you pointed out.
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Additionally, mast cells (MCs) were increased in the lungs of macaques with PTB
Consider including a quantification of the increase reported by Esaulova et al? It's always difficult to evaluate the importance of a finding like this without some appreciation of the magnitude of the change.
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eLife Assessment
In this useful study, the authors use published scRNA-seq data to highlight the importance of mast cells (MCs) in TB granulomas, reporting a comparative assessment of chymase- and tryptase-expressing MCs in the lungs of tuberculosis-infected individuals and non-human primates, with MC-deficient mice showing reduced lung bacterial burden and pathology during infection. Whilst the findings are helpful, the evidence to support conclusions is inconsistent across models and thus incomplete. Specifically, the data supporting a role for MCs in coordinating cytokine responses to modulate pathology, susceptibility to tuberculosis, and dissemination during infection are weak.
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Reviewer #1 (Public review):
Summary:
The study by Gupta et al. investigates the role of mast cells (MCs) in tuberculosis (TB) by examining their accumulation in the lungs of M. tuberculosis-infected individuals, non-human primates, and mice. The authors suggest that MCs expressing chymase and tryptase contribute to the pathology of TB and influence bacterial burden, with MC-deficient mice showing reduced lung bacterial load and pathology.
Strengths:
(1) The study addresses an important and novel topic, exploring the potential role of mast cells in TB pathology.
(2) It incorporates data from multiple models, including human, non-human primates, and mice, providing a broad perspective on MC involvement in TB.
(3) The finding that MC-deficient mice exhibit reduced lung bacterial burden is an interesting and potentially significant …
Reviewer #1 (Public review):
Summary:
The study by Gupta et al. investigates the role of mast cells (MCs) in tuberculosis (TB) by examining their accumulation in the lungs of M. tuberculosis-infected individuals, non-human primates, and mice. The authors suggest that MCs expressing chymase and tryptase contribute to the pathology of TB and influence bacterial burden, with MC-deficient mice showing reduced lung bacterial load and pathology.
Strengths:
(1) The study addresses an important and novel topic, exploring the potential role of mast cells in TB pathology.
(2) It incorporates data from multiple models, including human, non-human primates, and mice, providing a broad perspective on MC involvement in TB.
(3) The finding that MC-deficient mice exhibit reduced lung bacterial burden is an interesting and potentially significant observation.
Weaknesses:
(1) The evidence is inconsistent across models, leading to divergent conclusions that weaken the overall impact of the study.
(2) Key claims, such as MC-mediated cytokine responses and conversion of MC subtypes in granulomas, are not well-supported by the data presented.
(3) Several figures are either contradictory or lack clarity, and important discrepancies, such as the differences between mouse and human data, are not adequately discussed.
(4) Certain data and conclusions require further clarification or supporting evidence to be fully convincing.
-
Reviewer #2 (Public review):
Summary:
The submitted manuscript aims to characterize the role of mast cells in TB granuloma. The manuscript reports heterogeneity in mast cell populations present within the granulomas of tuberculosis patients. With the help of previously published scRNAseq data, the authors identify transcriptional signatures associated with distinct subpopulations.
Strengths:
(1) The authors have carried out a sufficient literature review to establish the background and significance of their study.
(2) The manuscript utilizes a mast cell-deficient mouse model, which demonstrates improved lung pathology during Mtb infection, suggesting mast cells as a potential novel target for developing host-directed therapies (HDT) against tuberculosis.
Weaknesses:
(1) The manuscript requires significant improvement, particularly in …
Reviewer #2 (Public review):
Summary:
The submitted manuscript aims to characterize the role of mast cells in TB granuloma. The manuscript reports heterogeneity in mast cell populations present within the granulomas of tuberculosis patients. With the help of previously published scRNAseq data, the authors identify transcriptional signatures associated with distinct subpopulations.
Strengths:
(1) The authors have carried out a sufficient literature review to establish the background and significance of their study.
(2) The manuscript utilizes a mast cell-deficient mouse model, which demonstrates improved lung pathology during Mtb infection, suggesting mast cells as a potential novel target for developing host-directed therapies (HDT) against tuberculosis.
Weaknesses:
(1) The manuscript requires significant improvement, particularly in the clarity of the experimental design, as well as in the interpretation and discussion of the results. Enhanced focus on these areas will provide better coherence and understanding for the readers.
(2) Throughout the manuscript, the authors have mislabelled the legends for WT B6 mice and mast cell-deficient mice. As a result, the discussion and claims made in relation to the data do not align with the corresponding graphs (Figure 1B, 3, 4, and S2). This discrepancy undermines the accuracy of the conclusions drawn from the results.
(3) The results discussed in the paper do not add a significant novel aspect to the field of tuberculosis, as the majority of the results discussed in Figure 1-2 are already known and are a re-validation of previous literature.
(4) The claims made in the manuscript are only partially supported by the presented data. Additional extensive experiments are necessary to strengthen the findings and enhance the overall scientific contribution of the work.
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