Mast cells promote pathology and susceptibility in tuberculosis

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 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.