Angiotensin-Converting Enzyme 2 Expression and Severity of SARS-CoV-2 Infection
Round 1
Reviewer 1 Report
I suggest the authors to include more recent articles in the introduction.
Please explain how the articles included in this review were selected.
Please rephrase 'Several medical societies worldwide have since advised against discontinuing these medications for hypertension''
What were the limitations of the present article?
Author Response
Reviewer 1 comments:
Comment 1: I suggest the authors to include more recent articles in the introduction.
Authors response: Statement and reference [2] added to the introduction (first paragraph, second sentence) to add context to the mechanism of viral infective mechanism.
“The S2 subunit then uses a hydrophobic fusion peptide domain to mediate the interaction between host and viral membranes”
Aside from this addition, in reviewing our 12 references included in the introduction section of the paper we feel these are contemporary publications related to the discovery and mechanisms of ACE2, its physiologic interactions, and the SARS-CoV2 and ACE2 interactions that offer reader an introduction to the theme of our review.
Comment 2: Please explain how the articles included in this review were selected.
Authors response: We have added a methods section to the manuscript describing our approach to the literature search strategy.
Comment 3: Please rephrase 'Several medical societies worldwide have since advised against discontinuing these medications for hypertension''
Authors response: We have rewritten this statement to the following sentence located on page 7 first paragraph of the “hypertension” section, last sentence…
“Medical guidance has since moved away from the early recommendations advising the discontinuation of ACEi and ARBs in COVID-19 infected individuals, and now recommend continuing these therapies if clinically indicated during COVID-19 infection.”
Comment 4: What were the limitations of the present article?
Authors response: We have added a limitations paragraph before the Conclusions section on Page 14.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
In this manuscript, the authors provided a detailed review based on the current understanding of ACE2 in SARS-CoV-2. This review will provided a good resource for the community regarding to the corresponding researches and deep understanding of COVID-19.
It better for the authors to make the conclusion more informative and add their own comments and insights.
Author Response
Reviewer 2 comments:
Comment 1: In this manuscript, the authors provided a detailed review based on the current understanding of ACE2 in SARS-CoV-2. This review will provided a good resource for the community regarding to the corresponding researches and deep understanding of COVID-19.
Authors response: We appreciate this comment. No changes were made to the manuscript in response to this comment
Comment 2: It better for the authors to make the conclusion more informative and add their own comments and insights
Authors response: We have added our conclusion section addressing the reviewers comments.
Author Response File: Author Response.pdf
Reviewer 3 Report
The manuscript of Sarah Alabsi is well-written and summarizes the numerous recent studies about the role of the ACE2 receptor in COVID-19 infection.
There are a few suggestions to slightly improve the review and make it more informative and interesting for the readers.
1. Recent scientific evidence supports that inhibition of ACE2 causes enhanced lung fibrosis (.doi: 10.1164/rccm.200912-1840OC, doi: 10.1165/rcmb.2012-0451OC). Since pulmonary fibrosis is a recognized complication of COVID-19, it should be noted that ACE2 inhibition is not a one-size-fits-all solution.
2. In this review, it is important to note the influence of smoking and alcohol consumption on ACE2 activation. Smith et al demonstrated that cigarette smoke causes a dose-dependent upregulation of ACE2 in rodents and human lungs (doi.org/10.1016/j.devcel.2020.05.012). e-cigarette vaping also increased ACE2 expression in lung tissue (doi: 10.1016/j.etap.2021.103656). Solopov et al showed that chronic alcohol consumption increases lung ACE2 expression and exacerbates SARS-CoV-2-like ARDS in h-ACE2 transgenic mice. These studies should be discussed in the paper.
3. It would be useful to provide a graphical abstract at the end of the manuscript describing the factors that activate the ACE2 receptor and trigger subsequent pathways leading to inflammation, etc.
4. It is worth making a table of recommended drugs at the end of the section with a brief description of their mechanisms of action and corresponding references.
Listen 15 / 5,000Translation results
Translation resreferences.
Author Response
Reviewer 3 comments:
Comment 1: Recent scientific evidence supports that inhibition of ACE2 causes enhanced lung fibrosis (.doi: 10.1164/rccm.200912-1840OC, doi: 10.1165/rcmb.2012-0451OC). Since pulmonary fibrosis is a recognized complication of COVID-19, it should be noted that ACE2 inhibition is not a one-size-fits-all solution.
Authors response: The following statement and associated references were added in the Pulmonary Diseases section of the manuscript on page 10, second paragraph, last sentence.
“However, it is worth noting that ACE2 expression changes alone do not provide an all-encompassing predictor of COVID-19 severity; pulmonary fibrosis, as sometimes seen in severe COVID-19 infection, has been shown to result from inhibition of ACE2 [84,85].”
Comment 2 : In this review, it is important to note the influence of smoking and alcohol consumption on ACE2 activation. Smith et al demonstrated that cigarette smoke causes a dose-dependent upregulation of ACE2 in rodents and human lungs (doi.org/10.1016/j.devcel.2020.05.012). e-cigarette vaping also increased ACE2 expression in lung tissue (doi: 10.1016/j.etap.2021.103656). Solopov et al showed that chronic alcohol consumption increases lung ACE2 expression and exacerbates SARS-CoV-2-like ARDS in h-ACE2 transgenic mice. These studies should be discussed in the paper.
Authors response: The following paragraph and associated references were added to the manuscript on page 11, first paragraph.
“While it is well-known that smoking is the leading cause of COPD [90], recent data has also shown that chronic tobacco smoke exposure is associated with a dose-dependent increase in ACE2 expression within both human and rodent lungs [91]. This is hypothesized to be due to the metaplasia of ACE-2 expressing secretory cells as a consequence of smoke inhalation. These expression differences are particularly noticeable in the lower airways [87]. Nicotine-containing vapor from e-cigarettes have also been directly linked to significantly increased ACE2 mRNA and protein expression in the lungs of male mice [92]. The reason for this sex-specific finding is still unknown.”
Comment 3: It would be useful to provide a graphical abstract at the end of the manuscript describing the factors that activate the ACE2 receptor and trigger subsequent pathways leading to inflammation, etc.
Authors response: We agree and have created one for our manuscript. Please see added figure titled “Graphical Abstract”
Author Response File: Author Response.pdf
Round 2
Reviewer 3 Report
The manuscript was improved. However, there are some missing comments.
1. The authors missed an important aspect of Comment 2. The authors discussed the effect of smoking and vaping on ACE2 activation. However, they missed the impact of alcohol. Solopov et al. (DOI: 10.1016/j.ajpath.2022.03.012) showed that chronic alcohol consumption increases lung ACE2 expression and exacerbates SARS-CoV-2-like ARDS in h-ACE2 transgenic mice. Friske et al. (DOI: 10.1101/2022.02.01.478685) demonstrated the increase of ACE2 in kidneys and liver) in rats with alcohol abuse. These studies still should be discussed.
2. There is still no figure with ACE2 pathways in the manuscript. It should be in the text. Probably, the authors accidentally did not attach it to the text, since there is a link in the text to Figure 1..
Author Response
Thank you. We have added a paragraph describing alcohol consumption/exposure and pulmonary ACE2 expression and lung damage risk and association to ARS-CoV-2 to the end of the pulmonary diseases section and before the medication section of the manuscript (see page 12).
