Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy

Round 1

Reviewer 1 Report

The review is concise and well written.

 

 

Author Response

Reviewer 1

 

Thank for reading my manuscript and your positive assessment.

 

Best wishes

Dr Rupert Holms

Reviewer 2 Report

 

In this manuscript, the author summarized the potential mechanism of long COVID (PASC) that is mediated by the inflammatory responses, the persistence expressed IL1b, TNF, and IL6, which is maintained by the loop of S100A8/A9 > TLR4/RAGE signaling, could majorly contribute to the COVID-19 caused sequelae. Lastly, the author suggested that the Ezrin Peptides HEP-1 & RepG3 may potentially be used as the therapeutic target for the PASC through their anti-inflammatory ability.

This manuscript is well organized, and the adequate references support the views, however, as the author described, both the lung monocytes infection and lung inflammation are critical for the PASC in the acute phase, if the author could talk a little more about the lung sequelae maybe make the review more solid. 

 

Author Response

Reviewer 2

 

Thank you for reading my Manuscript and your positive assessment. Following your suggestion, I have added a sentence and an additional recent reference to lung sequelae in Long-COVID PASC.

 

Best wishes

Dr Rupert Holms

Reviewer 3 Report

This manuscript provides a very comprehensive review of the underlying chronic self-stimulated in flammatory mechanism that causes Long-COVID and Post-Acute Sequelae of COVID (PASC). The molecular mechanisms of S100A8/A9 > RAGE and TLR4 Signaling are very well detailed, as well as the importance of the self-sustaining TLR4/RAGE-Loop. The diagrams of the two figures are very clarifying.  

Comments

1.      Data supporting the putative evidence of symptomatic relief (not confirmed yet by formal clinical trials) during treatment with ezrin peptide therapy in a few Long COVID / PASC patient volunteers are not provided. A more explicit reference to this aspect could increase the usefulness of this review.

2.      It could be very interesting to compare the possible usefulness of paquinimod, a specific inhibitor of S100A9 binding to TLR4, and resatorvid, a selective TLR4-inhibitor, with the therapeutic potential of ezrin peptides HEP-1 & RepG3

3.       Table 1 (page 3) lacks a heading and this could be completed

 

 

Author Response

Reviewer 3

 

Thank you for reading my Manuscript. In response to your suggestions:

1. I have added a brief description of the results in one ME-plus-Long-COVID patient who has been self-treating with ezrin-peptide RepG3-solution spray-inhalation and her self-reported symptom improvements.
2. In addition to the potential value of paquinimod and resatorvid in Long-COVID therapy, I have added a paragraph on a recent study using low dose naltrexone (a TLR4 inhibitor) in the treatment of Long COVID patients.
3. I have added a heading to Table 1 on page 3.

 

Best wishes

Dr Rupert Holms