http://orcid.org/0000-0002-2025-1937
Peer Review History
| Original SubmissionAugust 20, 2019 |
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Dear Prof. Dewals, Thank you very much for submitting your manuscript "Alcelaphine herpesvirus 1 genes A7 and A8 regulate viral spread and are essential for malignant catarrhal fever" (PPATHOGENS-D-19-01549) for review by PLOS Pathogens. Your manuscript was fully evaluated at the editorial level and by independent peer reviewers. The reviewers appreciated the attention to an important problem, but raised some substantial concerns about the manuscript as it currently stands. These issues must be addressed before we would be willing to consider a revised version of your study. We cannot, of course, promise publication at that time. I am returning your manuscript with two reviews. The reviewers came to different conclusions about the paper, as you will see. After reading the reviews and looking at the manuscript, I recommend Major Revision based on the critiques from the more critical reviews. I am sorry I cannot be more positive at the moment, however we are looking forward to receiving your revision. With a lot of work, the manuscript will be suitable for a resubmission, if you so wish to do so. Please pay particular attention to the following reviewer suggestions and give them due consideration: -Comments related to generation of a double mutant and the design of the rabbit studies to distinguish between access versus reprogramming of T cells -provide data for infection of bovine and rabbit T cells as described by reviewer 2 Your revisions should address the specific major and minor points made by each reviewer. In addition, when you are ready to resubmit, please be prepared to provide the following: (1) A letter containing a detailed list of your responses to the 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 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). 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. Additionally, to enhance the reproducibility of your results, PLOS recommends that you deposit your 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 We hope to receive your revised manuscript within 60 days. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by replying to this email. Revised manuscripts received beyond 60 days may require evaluation and peer review similar to that applied to newly submitted manuscripts. [LINK] We are sorry that we cannot be more positive about your manuscript at this stage, but if you have any concerns or questions, please do not hesitate to contact us. Sincerely, Paul D. Ling, Ph.D. Associate Editor PLOS Pathogens Erik Flemington Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens orcid.org/0000-0001-5065-158X Grant McFadden Editor-in-Chief PLOS Pathogens *********************** 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 paper describes an analysis of the attenuated AlHV1 strain WC11 and of the production and phenotypes of two BAC clone with stop mutations in genes deleted in WC11. The study is an important step forward in understanding the basis of attenuation in MCF viruses. It provides a well written and thorough analysis of the A7 and A8 genes, showing that these proteins mediate cell-free and cell-associated modes of propagation and that loss of either function leads to loss of virulence for MCF. The paper is suitable for publication in its current state but may benefit from minor modifications as described in the comments for authors. Reviewer #2: Myster and coauthors address the genetic differences between the pathogenic C500 and an attenuated WC11 strain of the Macavirus Alcelaphine herpesvirus 1 (AlHV-1). AlHV-1 and Ovine Herpesvirus 2 induces malignant catarrhal fever in susceptible ruminants and in rabbits. In cattle and rabbits, MCF is characterized by proliferation of CD8+ T-cells, a lymphoproliferative disease with strong similarity to the pathology caused by the New World primate viruses herpesvirus saimiri and ateles in tamarins and marmosets (which is overlooked in the introduction). They focus on one of three major differences between the pathogenic and the attenuated strains, the putative glycoproteins encoded by ORFs A7 and A8, which are both lacking in the attenuated WC11 strain. Individual bacmid-technology based mutants of each of A7 and A8 were generated in the C500 strain and compared to C500 and the A7 and A8 deleted WC11 in vitro and in vivo. Although no marker rescue viruses were made, the recombinants were sequenced and the data obtained with the mutants seems consistent. However, the important rabbit experiments do not discriminate between an inability to spread efficiently in the rabbits, failure to gain access to CD8 T cell populations or an inability to reprogram such cells toward lymphoproliferation. The authors provide an extensive comparison of the replicative behavior of C500, WC11 and two A7, one A8 mutants and mutants. Herein, depending on the cell culture system, the A7 mutants show an intermediate phenotype, increasing cell free propagation, while A8 seems to be required for cell associated spread. This may e.g. reflect alternative receptor usage for entry in these culture systems. Finally, rabbit experiments show that the C500 A7stop, A8stop and, as expected, attenuated WC11 do not induce MCF or CD8 T cell lymphoproliferation in this experimental model. They provide evidence all strains were able to infect rabbits, by serology and detection of viral genomes. The mutants and attenuated WC11, however, were only detectable at very low levels in the spleen, and not in circulating PBMC or lymph node. ********** 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: (No Response) Reviewer #2: Critical points - Why did they not make / analyze a double A7 and A8 stop mutant, corresponding to the situation in WC11? If the double mutant would show a replicative behavior even more similar to WC11, this would be important with respect to possible influence of the other two major genetic differences, which are located on the left and right genome ends, i.e. the absent putative ORF A1 and the variable ORFs A9.5 and A10? - The rabbit experiments do not discriminate between an inability to spread efficiently in the rabbits, failure to gain access to CD8 T cell populations or an inability to reprogram such cells toward lymphoproliferation. There was no monitoring for viral spread (genome copies in blood?) during the infection experiment, only at endpoint. Thereby, vastly different time points are compared, and the low levels of virus genomes observed with A7 and A8 stop mutants and WC11 may reflect long term immune control of latent infection, compared to an acute disease with multiple virus genomes in the CD8 population. - In vitro infection (or by cocultivation) of bovine or rabbit CD8 T-cells with the EGFP marker viruses (or by infection followed by PCR) could demonstrate whether this is a matter of entry/access to this population. - Cells injected intravenously, if not phagocytosed or killed the immune cells, may end in small vessels of lung, spleen, liver etc. where they may infect neighboring tissue, not necessarily T cells. Similarly, after intranasal infection, local infection and spread is critical, and T cells are unlikely to be the first cells encountering a pathogen. ********** 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: Minor issues Line 150. Please be explicit. Clarify whether the LUR or TR copies are meant Line 153. Please specify German WC11 stock to distinguish from the stock sequenced here Line 157-8. please clarify text here, as this point may be unclear to some readers Line 160. "during multiple passages" rather than ‘following multiple passages’ Lines 194-209. the authors should acknowledge previous publications describing the similarity between A7/A8 and gp42/350 (Russell, 2014. In: Manual of Security Sensitive Microbes and Toxins. CRC Press; https://www.crcpress.com/Manual-of-Security-Sensitive-Microbes-and-Toxins/Liu/p/book/9780367378745); and the function of the A8 homolog Ov8 in membrane fusion (AlHajri, 2017. J.Virol. 91:e02454-16. https://doi.org/10.1128/JVI.02454-16). Line 217. In the BAC mutation description it is important that you show that both TR and LUR gene copies of A7 & A8 were mutated, or explain why this was not required Line 251. Fluorescence microscopy and use of antibody 15A are not mentioned in methods Line 300. is ref 43 intended? Maybe should be 35? Line 302. While it’s completely acceptable to choose to study A7/A8, I think it is important that the authors mention why there was no focus on A1 in this work. Line 342. I don’t feel that sup fig 4 is necessary Reviewer #2: Minor points: - Figs 1,3,4 are more suitable for supplement. - For intravenous injection, infected tissue culture cells are used, while the authors refer to pfu for intranasal infection? ********** 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: George C. Russell Reviewer #2: No |
| Revision 1 |
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Dear Prof. Dewals, We are pleased to inform you that your manuscript 'Alcelaphine herpesvirus 1 genes A7 and A8 regulate viral spread and are essential for malignant catarrhal fever' 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 within two working days 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, Paul D. Ling, Ph.D. Associate Editor PLOS Pathogens Erik Flemington 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): |
| Formally Accepted |
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Dear Prof. Dewals, We are delighted to inform you that your manuscript, "Alcelaphine herpesvirus 1 genes A7 and A8 regulate viral spread and are essential for malignant catarrhal fever," 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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