Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.
Read more about eLife’s peer review process.Editors
- Reviewing EditorBavesh KanaUniversity of the Witwatersrand, Johannesburg, South Africa
- Senior EditorBavesh KanaUniversity of the Witwatersrand, Johannesburg, South Africa
Reviewer #1 (Public Review):
Summary:
Their findings elucidate the mechanisms underlying 2-AA-mediated reduction of pyruvate transport into mitochondria, which impairs the interaction between ERRα and PGC1α, consequently suppressing MPC1 expression and reducing ATP production in tolerized macrophages. While the data presented is intriguing and the paper is well-written, there are several points that warrant consideration. The authors should enhance the clarity, relevance, and impact of their study.
Strengths:
This paper presents a novel discovery regarding the mechanisms through which PA regulates the bioenergetics of tolerized macrophages.
Weaknesses:
The relevance of the in vivo model to support the conclusions is questionable. Further clarification is needed on this point.
Reviewer #2 (Public Review):
Summary:
The study tries to connect energy metabolism with immune tolerance during bacterial infection. The mechanism details the role of pyruvate transporter expression via ERRalpha-PGC1 axis, resulting in pro-inflammatory TNF alpha signalling responsible for acquired infection tolerance.
Strengths:
Overall, the study is an excellent addition to the role of energy metabolism during bacterial infection. The mechanism-based approach in dissecting the roles of metabolic coactivator, transcription factor, mitochondrial transporter, and pro-inflammatory cytokine during acquired tolerance towards infections indicates a detailed and well-written study. The in vivo studies in mice nicely corroborate with the cell line-based data, indicating the requirement for further studies in human infections with another bacterial model system.
Weaknesses:
The authors have involved various mechanisms to justify their findings. However, they have missed out on certain aspects which connect the mechanism throughout the paper. For example, they measured ATP and acetyl COA production linked with bacterial re-exposures and added various targets like MCP1, EER alpha, PGC1 alpha and TNF alpha. However, they skipped PGC1 alpha levels, ATP and acetyl COA in various parts of the paper. Including the details would make the work more comprehensive.
The use of public data sets to support their claim on immune tolerance is missing. Including various data sets of similar studies will strengthen the findings independently.
