Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper focuses on the key host determinants associated with the clinical severity of human influenza virus infection, systematically reviewing the research progress in individual risk factors, host genetic factors, and host cellular determinants. It also analyzes the current status and challenges of prevention, control, and treatment in the context of the prevailing influenza epidemic. The research direction holds significant clinical and public health importance, with a comprehensive literature review and a clear logical framework. The manuscript is recommended for acceptance after minor revisions.

1. The descriptions of Figure 1 and Figure 2 lack detailed clarification of the interaction relationships and hierarchical roles among the factors shown, and the typo of "ANP328" (should be ANP32B) in Figure 2 needs correction to enhance the accuracy and readability of the visual materials.
2. Some conclusions about the correlations between host factors and severe influenza are stated too absolutely without specifying the research models (e.g., animal models) or sample limitations, and additional qualifying statements are required to improve the scientific rigor of the manuscript.
3. The discussion section insufficiently elaborates on the specific clinical translational value of the identified key host factors, and supplementary content on their application as severe illness predictive biomarkers and therapeutic targets, as well as guidance for vaccine optimization, is needed to strengthen the practical significance of the study.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Flora De Conto in this review report an update on the key host factors involved in severe influenza, in order to allow a better understanding of their roles at the cellular level in the outcomes of the infection. The reported data are of interest and could be a clinical relevance in the influenza virus respiratory viral infection. However, to make it more interesting and to acquire clinical relevance there are some points to be improved.

Main points

1- At line 88, for the argument reported,  the section 2. “Individual factor that….” should be changed in “Individual subject factor that…”

2- According this reviewer, additional table reporting the main factor described inherent to the subject categories could be of help to the description of the data.

3- at line 161 it is reported genetic factor involved in the IFN responses. According this reviewer, a table reporting these information could be of help.

4-  line 231: this phrase is not clear and should be rewritten. What is the meaning of personalized medical intervention related to the SNP?

5- Discussion: the discussion is mainly focused on the vaccination features. Only at lines 506-511 there are a comment on the matter of the aim of the review. It could be better if the author considers to remodel discussion on this aim. Otherwise, describe the effect on vaccination in host factor in the manuscript.

6- It could be interesting if the author comments the effect of influenza virus superinfection or coinfection with different respiratory virus in the host factors involved in outcome of infection. Are there any data regarding this?

Minor points

1- line 29: the term “segmented” should be added to the genome structure of influenza virus.

2- line 220-222: this phrase is a repetition and could be erased.

3- in the legend of figure 2 it should be reported all the complete name of the acronyms illustrated in the figure.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have substantially improved the manuscript. There is only a last point regarding the respons to previous point 6 (It could be interesting if the author comments the effect of influenza virus superinfection or coinfection with different respiratory virus in the host factors involved in outcome of infection. Are there any data regarding this? Response: I thank the Reviewer for this important and interesting comment, that deserve future in-depth research. As reported in the new version of the Discussion section, some cellular factors hijacked by the influenza virus are in common with RSV and Sars-CoV-2 in case of severe infections (see lines 590-603). To my knowledge, no data are so far available regarding superinfection and co-infection). This reviewer agrees with the authors on the scanty data on in vivo coinfection and superinfection of influenza virus and other respiratory viruses. However, an additional comment/suggestion based on few published  in vitro studies on this matter, can be done to implement the comment at line 590-603 by the authors. This authors suggestion could be relevant to understand the different outcome severity of the diseases produce in co-infection or superinfection.

Author Response

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Author Response File: Author Response.pdf