The Common Mucosal System Fifty Years on: From Cell Traffic in the Rabbit to Immune Resilience to SARS-CoV-2 Infection by Shifting Risk within Normal and Disease Populations

Round 1

Reviewer 1 Report

In this article, Clancy et al. present a comprehensive review of the role of the Common Mucosal Immune system (CMS) in immune protection and its potential to modulate the impact of vaccination-induced protection against airway infection. The manuscript is well-structured and thoroughly examines the existing literature on the subject. The article also provides a clear summary of the studies included in the review and a thorough analysis and synthesis of the current literature on the topic. The author should address the following concerns to strengthen the paper further.

 

 

Major concerns:

1. The review focuses primarily on the CMS and its role in immune protection. While this is an important topic, the study could be strengthened by discussing other factors that influence the immune response to SARS-CoV-2 infection, such as host genetics, comorbidities, and the role of other components of the immune system.
2. The review could benefit from a more critical analysis of the studies included. For example, discussing the limitations of the studies, any conflicting findings in the literature, and the quality of the evidence presented.
3. The manuscript relies heavily on a few key studies. While these are likely essential contributions to the field, it would be beneficial to include a broader range of sources to provide a more comprehensive overview of the topic.
4. Some sections of the manuscript could benefit from improved organization and clarity. For instance, the discussion section jumps between different topics, making it difficult to follow the author's line of reasoning.
5. While the author discusses future directions in the conclusion, this could be expanded upon. Specifically, the author could discuss potential strategies for leveraging the CMS to improve immune response to SARS-CoV-2 and other respiratory pathogens.
6. The introduction provides an adequate background and clearly states the study's purpose. It could be improved by providing more context about the current state of knowledge regarding the CMS and its role in immune protection. 
7. The discussion provides a reasonable interpretation of the reviewed literature and places them within the context of the existing knowledge. The author could further explore the implications of these findings for future research and potential clinical applications. Specifically, How might these insights about the CMS and immune protection be applied in developing vaccines or treatments for SARS-CoV-2?

 

 

Minor concerns:

1. Line 24: The question "Why do most infected with SARS-CoV-2 virus have few symptoms, yet a small number get severe disease?" This sentence is unclear and should be rephrased for clarity.
2. Line 46: "Citation: To be added by editorial staff during production." - This line should be removed in the final manuscript.
3. Line 263: "Variable Univariable Association" - This sentence is unclear and should be rephrased for clarity.
4. Line 317: "Our observations extended the previous report by further identifying fibrosis in NAFLD as the main driver of this relationship." - This sentence is unclear and should be rephrased for clarity.

Minor punctuation and spelling errors exist throughout the manuscript and I recommend thorough proofreading.

Author Response

(i) Have corrected at lines 24 and 46.

 

(ii) I could not identify the issues of concern at lines 263 and 317. Please identify again and I will fix them.

 

(iii) I will address these 6 major comments collectively, as they overlap, and have been addressed in similar vein.

First, the review was never meant to be a comprehensive overview of oral vaccines or probiotics - I had attempted to separate the physiological stimuli within airway secretions aspirated into the gut, from vaccines, probiotics and other microbial products used to address mucosal immunity. However the points made are valuable as it is a confusing area - indeed oral vaccines use different mixes of effector mechanisms, and I am sure that this will become clearer as time goes. I have therefore included several more recent Reviews on mucosal vaccination, indicating their value in identifying specific mechanisms and how they each may have value. The overwhelming observation is that they all seem unaware of the importance of delivery of T and B cells in development of immune protection. The point of the current review. I point out that those focussing on vaccines eg Holmgren and Cholera vaccines, entirely look at antibody, which you note is rarely seen with enhanced CMS, where T cell delivery is critical (and discussed). Interestingly, in these recent reviews, in situ T cells are discussed as though they come from no where, when almost certainly they were delivered through the CMS. Also, largely ignored, has been the dominant role of T reg cells and down regulation, though the impact of this regulatory system is recognised by these reviewers. I have prepared a long paragraph in the Discussion, which by its placement hopefully helps address several concerns. First, organisation. It sits between sections, giving hopefully a better and clearer structure. Second, it increases sources, enables better critical assessment, broadens sources, and introduces the vaccine challenges. This covers the comment re adding more current references to the “Introduction” (I chose to place these comments in “Discussion”).

 

(iii) I have modified the “Future” section, but similar comments have been added in brief elsewhere in the text.  

 

I would be very happy to add further changes, if I have failed to address issues of importance. My point is that there has been a major blindness to the “big picture” of airway immunity, with respect to delivery of T cells as the critical factor driving immune protection, that this is an imperfect system taht can be reinforced very simply by ensuring a more controlled delivery of the physiological stimulus: respiratory microbiome, and with major clinical benefit. I have stressed the potential for enhanced vaccine-induced immunity, adding a new reference showing probiotics can increase vaccine induced immunity, but as is a feature of probiotics, outcomes are variable. optimised CMS-dependent airway immunity likely will be far more predictable. While oral vaccines and probiotics “use” mechanisms common to the physiological stimuli (here called immunobiotics), they are very different. Immunobiotics have precise requirements, and relate to already established immunity - they just improve it specifically, but (by activation of learned innate immunity) act non-specifically to reduce “load “ of the microbiome. This review focusses on these areas, serving only to be differentiated from oral vaccines. It’s is a very powerful protective system.

Reviewer 2 Report

In the manuscript "IMMUNE RESILIENCE TO SARS-CoV-2 INFECTION BY SHIFTING RISK WITHIN NORMAL AND DISEASE POPULATIONS", the author has adequately described the Common Mucosal System (CMS) as well as the role of NTHi as an immunobiotic. However, the following points need to be added/rectified:

1.  In line no. 119, the full form of PNG must be included.

2. Line no. 123 should be in sentence case.

3. Line no. 151 should be in bold and properly spaced if the author intended it to be a separate section.

4. The author must include a schematic illustration to explain the methods of delivery of immune protection to airway mucosa via CMS and also list out the limitations of the same for better understanding and grasping by the readers.

 

 

Author Response

(i) I have made corrections re pages 119,123, and 151.

(ii) I have added a diagram to illustrate the role of the CMS, with added points to link with numbers on the diagram.

Round 2

Reviewer 2 Report

The following changes are needed to be done to consider the paper for publication:

1. Line no. 152 should be in bold and properly spaced as a title indicative of a separate section.

2. The figure is not good, it must be replaced with high resolution illustration prepared using online or offline drawing/ illustration builder tools.

Author Response

I have addressed the first of the issues raised, but have a real problem with the diagram. Frankly I do not think it is needed, as the text explanation is very clear. Second, I included a very clear diagram as initially requested by the reviewer who believes it is not good enough. I have no idea as to how to produce the the line diagram he/she suggests. I have no problem with the idea, I just would not know where to start. Perhaps you could ask your experts as to whether the diagram would print clearly or whether there is any trick they can use to make the diagram clearer? That is, if you agree it is needed.