PPATHOGENS-D-26-00501

Reduced inflammatory and Th1 transcriptional profiles in geriatric versus adult cotton rats infected with respiratory syncytial virus

PLOS Pathogens

Dear Dr. Miller,

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Kind regards,

Barry Rockx

Academic Editor

PLOS Pathogens

Thomas Hoenen

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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Reviewers' Comments:

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 is a very well written manuscript addressing an important question of the different pathogenesis of RSV infection in the geriatric population. The methodology used, analysis, and conclusions are appropriate. Other than some minor comments related to writing there are no concerns.

Reviewer #2: Miller et al. use RNA-seq and pathway analysis on lung tissue from the geriatric RSV cotton rat model, which closely mimics the human model, to characterize host immune responses with respect to RSV clearance and low neutralizing antibody levels. The authors observed significant differences in the DEGs and the pathway analysis, wherein the adult cotton rats mounted an increase in pro-inflammatory cytokine pathways compared to the geriatric cotton rats. They demonstrated that splenocytes of the adult RSV-infected animals mounted a Th1 polarization upon stimulation, while the geriatric animals mounted a Th2 response.

The study was overall well-designed and written. The authors successfully demonstrate that geriatric cotton rats mount an impaired Th1 response in comparison to adult cotton rats. The authors should include a figure showing the comparison of the DEGS adult vs geriatric animals and list all the DEGS as a supplementary figure. This is critical information for the field, which would help future studies.

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Part II – Major Issues: Key Experiments Required for Acceptance

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Reviewer #1: None

Reviewer #2: The authors should include a figure showing the comparison of the DEGS adult vs geriatric animals and list all the DEGS as a supplementary figure. This figure should be relatively easy to generate, as the data already exists.

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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: -The results are reported sometimes in the past tense and other times in present tense. Perhaps normalize everything to the past tense?

-The sentence on lines 134-137 is somewhat confusing and should probably be reworded.

-The sentence on lines 121-122 should be revised with more details provided on what was actually done.

-Fig.1 legend. Replace “in whole lung” with “in the lung”, as technically only the left lung was used for analysis. The same should be done for the legend for Fig. 2.

-Perhaps provide an explanation for why IL-12p35 and not IL-12b was chosen for the digital PCR analysis?

-The definition of “geriatric” cotton rats is different in different parts of the manuscript. In “Methods” it is listed as >8 months old, in the legend to Fig.5 as “>12 months of age”. Making it more consistent would help the reader.

-On line 379 the word “detectable” should be added before “IL-4”. The word “detectable” (or “elevated) should also be considered on line 380 before the word “secretion”.

Reviewer #2: None

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Reviewer #1: No

Reviewer #2: No

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Dear Dr. Miller,

We are pleased to inform you that your manuscript 'Reduced inflammatory and Th1 transcriptional profiles in geriatric versus adult cotton rats infected with respiratory syncytial virus' has been provisionally accepted for publication in PLOS Pathogens.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens.

Best regards,

Barry Rockx

Academic Editor

PLOS Pathogens

Thomas Hoenen

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

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The author has sufficiently addressed the reviewer comments.

Reviewer Comments (if any, and for reference):