PONE-D-21-29749On the Possibility of Oscillating in the Ebola Virus Dynamics and Investigating the Effect of the Lifetime of T lymphocytesPLOS ONE

Dear Dr. Asgari,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The review below raises some concerns about the model and identifies areas in which results from the cellular automata model should be analyzed in more detail. 

Please submit your revised manuscript by Dec 24 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Steven M. Abel, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors of “On the Possibility of Oscillating in the Ebola Virus Dynamics and Investigating the Effect of the Lifetime of T lymphocytes” describe a cellular automata (CA) model to represent the spread of Ebola virus in lymph nodes.

While this is an important topic and the authors present interesting results, there are some questions and concerns about the model, as well as potentially some missed opportunities to take advantage of what CA models can offer.

1. One strength of CA models is to offer spatial insights, yet there are no spatial results given beyond figure 2. One important question arising from their results is: what does the spatial distribution of infected cells look like in simulations that oscillate?

2. Another missed opportunity lies in comparing results between the ODE and CA models (which the authors state that they will do (p4), and mention again on p16) but do not present any results for). It would be interesting to see if the oscillations arise because of the spatial nature of CA models, or if this is something that is preserved from the ODE model?

3. Another key feature of CA models is their stochasticity. The authors write that they average 50 simulations, which raises a few questions

a. Why not include standard error/standard deviation in their figures? Only showing the average does not represent the full range of possible outcomes and makes it difficult to evaluate the impact of stochasticity in this system.

b. When they report oscillations in their average values (e.g. Fig 8) – does that imply that all of the individual simulations oscillate at the same frequency and amplitude?

4. In the introduction, the authors said that T cells are initial targets. But healthy cells which can be infected and T cells are two different groups in their model. Infected cells with T cells around can change either to healthy cells or T cells. It's unclear what is the relationship (and the difference) between healthy cells and T cells in the model.

5. There are many different types if T cells with different functions. Please specify the type of T cell considered in this model.

6. In the results section a lot of different scenarios are tested, with different parameters and movement settings, which is good. But some problems exist:

a. Influence of PH and PD are specifically tested with different values, but it is unclear why those two are chosen, not PI and PT.

b. PI and PT are also changing from fig. 3 to fig. 8. But the change is not specifically mentioned. What is the influence of these parameters?

c. In fig. 6 C, when the death rate of infected cells is high, instead of infected cells, T cells die out. This is quite counter intuitive and warrants more discussion. Also, it is surprising that infected cells can be maintained at low level in the absence of T cells.

d. There are lots of details given describing what the figures show, but this type of discussion distracts from the main idea that's being delivered. There should be some more conclusive statement summarizing/synthesizing the findings from each scenario.

e. The oscillations are a key feature of their results, but an explanation of the source of oscillations is lacking.

7. The second paragraph in the results section mostly summarizes their results again. Some of this discussion would be better included in the results section as it doesn’t really help the reader connect their findings to the broader field.

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Reviewer #1: No

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PONE-D-21-29749R1On the Possibility of Oscillating in the Ebola Virus Dynamics and Investigating the Effect of the Lifetime of T lymphocytesPLOS ONE

Dear Dr. asgari,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the minor concerns raised below.

Please submit your revised manuscript by Apr 04 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Steven M. Abel, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have made significant updates to improve the manuscript. Two minor comments based on their revisions are below.

The addition of figure 9 is very helpful. The authors explain the cases where the infected cells go to zero as being because of starting with only one infected cell. But don’t all simulations start with one infected cell?

It is still not clear to me what the parameter PT represents and what it means biologically. Does it represent T cell proliferation in response to interaction with an infected cell? Does (1-PT) represent regeneration of the dead target cell?

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7. 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

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

On the Possibility of Oscillating in the Ebola Virus Dynamics and Investigating the Effect of the Lifetime of T lymphocytes

PONE-D-21-29749R2

Dear Dr. asgari,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Steven M. Abel, Ph.D.

Academic Editor

PLOS ONE

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