https://orcid.org/0000-0001-5897-4383
Peer Review History
| Original SubmissionDecember 23, 2020 |
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Dear Dr. Iovino, Thank you very much for submitting your manuscript "Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations. While all reviewers feel that the manuscript is considerably improved, reviewer 2 maintains concerns regarding the strength of data supporting interactions of Ply and RrgA with beta-actin. These concerns should be addressed experimentally. Reviewer 1 has minor comments that should be addressed in the discussion as well. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. When you are ready to resubmit, please upload the following: [1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out [2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments. Sincerely, Carlos Javier Orihuela, PhD Associate Editor PLOS Pathogens Michael Wessels Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************** While all reviewers feel that the manuscript is considerable improved, reviewer 2 maintains concerns regarding the strength of data supporting interactions of Ply and RrgA with beta-actin. These concerns should be addressed experimentally. Reviewer 1 has minor comments that should be addressed in the discussion as well. Reviewer Comments (if any, and for reference): Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: This manuscript investigates the role of pneumococcal interactions with neuronal ß actin in the course of brain damage in meningitis. It is well known that there are many mechanisms by which pneumococci can kill cells, including neurons. This manuscript describes a new one. The authors present a very plausible scenario that a pneumococcal pilus brings the bacteria close to the neuronal membrane and this increases the toxicity of the cytotoxin Pln; these steps involve interactions with cell surface ß actin. The experiments follow a logical sequence and the data is solid, well controlled and strongly support the conclusions. Minor Comments: 1) Abstract: Mechanisms of neuronal damage in meningitis have been extensively studied in many labs for decades. While this paper presents a new one, it is perhaps inaccurate to begin the abstract with “little is known about mechanisms that lead to neuronal death” 2) Introduction: Studies from this laboratory group have suggested that pilus is present on only ~20% of clinical pneumococcal strains. This should be made clear and any data indicating if pili are more abundant in meningeal strains should be cited. This would place the new mechanism in the context of the likelihood that in a given patient, the deployment of strategies against the mechanisms of damage shown in this study may not be commonly operative. 3) The studies with ß actin are particularly strong and innovative. The careful and detailed microscopy is highly informative and supports the conclusions. 4) Most of the studies shown are with a neuronal cell line. There are many different neuronal types; which one does this cell represent? In clinical meningitis, it is known that hippocampal neurons are found to be damaged more often than cortical neurons. Does the mechanism described in this paper suggest a reason for this variable susceptibility? Reviewer #2: The authors showed that neuronal cell death in pneumococcal meningitis is caused by the interaction of the pneumococcal virulence factor Ply and the pilli factor RrgA with beta-actin. Furthermore, they also showed that pneumococci promoted RrgA- and Ply-dependent actin depolymerization, leading to Ca2+ influx and cell death. The results in this paper are too indirect to support their hypothesis, and mechanistic approach to elucidate the significance of Ply- and RrgA- interaction with actin should be done. Reviewer #3: The authors have taken great care in addressing the concerns of the reviewers, including providing additional data. ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: None Reviewer #2: 1. The direct interaction of Ply D4 and actin should be required, and the author should demonstrate whether single amino acid substituted actin-binding deficient Ply-complemented pneumococci fails to increase the amount of β-actin exposed to the cell surface and dampens the RrgA adherence to neuron, Ca2+ influx and cell death without pore-forming activity. It is critical issue to demonstrate their hypothesis directly. 2. Similarly, the author should demonstrate whether single amino acid substituted actin-binding deficient RrgA-complemented pneumococci fails to Ca2+ influx and cell death. It is critical issue to support their hypothesis directly. Reviewer #3: None. ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: Listed in Part 1 Reviewer #2: 1. Quality of images are too poor. 2. Fig. S12 should be included in main text. Reviewer #3: None ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Elaine Tuomanen Reviewer #2: No Reviewer #3: No Figure Files: While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Data Requirements: Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5. Reproducibility: To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plospathogens/s/submission-guidelines#loc-materials-and-methods |
| Revision 1 |
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Dear Dr. Iovino, We are pleased to inform you that your manuscript 'Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Carlos Javier Orihuela, PhD Associate Editor PLOS Pathogens Michael Wessels Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens *********************************************************** Reviewer Comments (if any, and for reference): Reviewer's Responses to Questions Part I - Summary Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer #1: The authors have addressed most of the requirements put forward by the reviewers. Reviewer #2: (No Response) ********** Part II – Major Issues: Key Experiments Required for Acceptance Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject". Reviewer #1: Completed as listed Reviewer #2: All of my concerns have been addressed. ********** Part III – Minor Issues: Editorial and Data Presentation Modifications Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer #1: (No Response) Reviewer #2: None ********** PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No |
| Formally Accepted |
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Dear Dr. Iovino, We are delighted to inform you that your manuscript, "Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin," has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Michael Malim Editor-in-Chief PLOS Pathogens |
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