Leveraging publicly available coronavirus data to identify new therapeutic targets for COVID-19

Stacy L. Sell; Donald S. Prough; Harris A. Weisz; Steve G. Widen; Helen L. Hellmich

doi:10.1371/journal.pone.0257965

Peer Review History

Original SubmissionMarch 19, 2021
25 May 2021 Decision Letter - Prasenjit Mitra, Editor PONE-D-21-09155 Leveraging publicly available coronavirus data to identify new therapeutic targets for COVID-19 PLOS ONE Dear Dr. Hellmich, 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. Please make the necessary changes as indicated by the reviewer. Please submit your revised manuscript by Jul 09 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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If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ [Note: HTML markup is below. Please do not edit.] 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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 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: Yes ****** 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 ****** 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 have undertaken bioinformatic analysis of four coronavirus datasets to assess the differential expression of various anti-viral and pro-viral genes. The results have been discussed appropriately taking into consideration the numerous gene obtained from the analysis. The following points may be addressed: 1. A short clinico-pathological comparative description of MERS to COVID & SARS CoV 1 to SARS CoV 2 indicating the probable relevance of the genes discussed would be appropriate. 2. Are there any original studies which have explored the temporal suppression of antiviral immune response in COVID when compared with other viral infections ? This may substantiate the temporal suppression of antiviral immune response observed in the analysis. 3. Line 254: How miR-139-3p expressed at low levels in both SARS-CoV-1 and SARS-CoV-2 cells as well as untreated control cells can be attributed to provide permissive environment ? 4. Line 364: It is unclear how the present analysis identify genes involved in COVID-19 induced chronic symptoms, rather it will give insight into COVID associated complication. ****** 6. 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. https://doi.org/10.1371/journal.pone.0257965.r001
Revision 1
8 Jul 2021 Author Response Reviewer #1: The authors have undertaken bioinformatic analysis of four coronavirus datasets to assess the differential expression of various anti-viral and pro-viral genes. The results have been discussed appropriately taking into consideration the numerous gene obtained from the analysis. The following points may be addressed: 1.A short clinico-pathological comparative description of MERS to COVID & SARS CoV 1 toSARS CoV 2 indicating the probable relevance of the genes discussed would be appropriate. Response: Respectfully, we would like to point out that the original intent of this in silico analysis was to identify biologically relevant host genes affected by the viral pathogens from previously deposited coronavirus datasets that may prove to be novel therapeutic targets and infer from published reports their functional relevance to host defenses. Our literature analysis showed that many of these pro-viral or antiviral host response genes were also targeted by many diverse viral pathogens known to infect human hosts. We did not intend to describe a comprehensive comparison of MERS, SARS-CoV-1 and SARS-COV-2 since hundreds of such comparisons have been published in the past year and a half since the beginning of the Covid-19 pandemic; our focus was on identifying novel gene targets of these viruses. To our knowledge, our in silico analysis of the gene targets of coronavirus-induced host genes is among the first to show that these host response genes are also implicated in the pathogenesis of many other diverse viruses; the implication is that broad spectrum antiviral drugs that are efficacious for other viral pathogens may be effective for Covid-19 patients but this remains to be proven in future studies. We also believe that the functional relevance of the genes have been addressed throughout the manuscript and further discussion would veer upon more speculation than necessary. 2.Are there any original studies which have explored the temporal suppression of antiviralimmune response in COVID when compared with other viral infections ? This may substantiatethe temporal suppression of antiviral immune response observed in the analysis. Response: During the time we did the in silico analysis of these coronavirus datasets and wrote the manuscript, there were some unpublished reports in preprint servers suggesting that SARS-CoV-2 did indeed suppress the antiviral immune response as our analysis indicated. Most did not address the temporal suppression as described in our manuscript. Only recently were such reports published in peer-reviewed journals. We now cite, in the manuscript, one such supporting study by Finkel et al., that was recently published in Nature (https://www.nature.com/articles/s41586-021-03610-3). 3.Line 254: How miR-139-3p expressed at low levels in both SARS-CoV-1 and SARS-CoV-2cells as well as untreated control cells can be attributed to provide permissive environment ? Response: In other words, since miRNA expression is inversely related to their gene targets, i.e. if high, their target genes are suppressed and if low, like miR-139-3p, their gene targets are highly expressed or upregulated, the naturally occurring expression of some host genes that are the targets of these miRNAs may help pathogenic viruses infect host cells. Since that was a speculative comment on our part, we clarified this statement in the manuscript. What we meant was “ viruses could exploit and coopt the endogenously expressed host proteins to facilitate entry into host cells and favor the replication of viral proteins”. 4.Line 364: It is unclear how the present analysis identify genes involved in COVID-19 inducedchronic symptoms, rather it will give insight into COVID associated complication. Response: The chronic symptoms described in the manuscript have been extensively documented in many published studies of hundreds of Covid-19 patients this past year and some of those studies are cited in our manuscript. We believe, based on the literature analysis of the function of the coronavirus-induced host gene targets, that not only does our study provide insight into Covid associated complications but also insight into the chronic symptoms reported by so called “Covid long haul” patients. For example, loss of smell is a frequently reported chronic health problem in Covid-19 survivors and the persistent symptoms of myocarditis, diabetes and so-called brain fog in Covid-19 survivors are among the chronic symptoms that can be linked to the dysregulated expression of some of the coronavirus gene targets mentioned in our study. We would like to point out that this study was not meant to be a comprehensive treatise of Covid-19-associated gene changes in human hosts; our intent was to identify novel gene targets that could be therapeutically targeted with existing or new coronavirus drugs in development. The four coronavirus datasets analyzed in this study represent the three recent and current causes of severe coronavirus outbreaks in human populations and were chosen without any other preconceived bias; we only present examples from the literature supporting the likely functional roles of the viral gene targets and we will leave it up to the scientific readership to infer the association of these genes with reported Covid symptoms based on the analysis presented in our study. Attachments Attachment Submitted filename: Response to Reviewers Covid MS PlosOne 6July2021.pdf https://doi.org/10.1371/journal.pone.0257965.r002
15 Sep 2021 Decision Letter - Prasenjit Mitra, Editor Leveraging publicly available coronavirus data to identify new therapeutic targets for COVID-19 PONE-D-21-09155R1 Dear Dr. Hellmich, 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. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Prasenjit Mitra, MD, CBiol, MRSB, MIScT, FLS, FACSc, FAACC Academic Editor PLOS ONE Additional Editor Comments (optional): 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: All comments have been addressed ******** 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: (No Response) ****** 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 https://doi.org/10.1371/journal.pone.0257965.r003
Formally Accepted
20 Sep 2021 Acceptance Letter - Prasenjit Mitra, Editor PONE-D-21-09155R1 Leveraging publicly available coronavirus data to identify new therapeutic targets for COVID-19 Dear Dr. Hellmich: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Prasenjit Mitra Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257965.r004

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