Programmed Cell Death in SARS-CoV-2 Infection: A Short Review
David J. Blake
Round 1
Reviewer 1 Report
This manuscript identifies the mechanisms of apoptosis induced by SARS-CoV-2 infections. The paper is helpful to the scientific community because it focuses on a single endpoint (cell death) related to SARS-Cov-2 infections. The reviewer has a few minor edits and suggestions prior to publication.
- abstract line 15 - add in the word "the" prior to hyperinflammatory
- Introduction line 32 humans should be plural
- Introduction line 39 "is the latest one" is too vernacular, please reword
- Introduction line 40 - is an enveloped virus with glycoproteins
- Introduction line 49 "to deal with" also too vernacular, reword
- Apoptosis line 69, only certain viruses (naked) would benefit from apoptosis in order to release virions, right? Enveloped viruses in certain cases do not want apoptosis to occur due to the necessary production of membranes? This could be clarified.
- ORF3a - is it know how Orf3a induces apoptosis? If not, then this should be stated directly.
- ORF6 line 139 "the" membrane
- ORF 8 line 156 - IFN-beta correct?
Author Response
1. abstract line 15 - add in the word "the" prior to hyperinflammatory
Answer: We have added the word “the” as suggested.
2. Introduction line 32 humans should be plural
Answer: Correction has been made.
3. Introduction line 39 "is the latest one" is too vernacular, please reword
Answer: The line has been reworded.
4. Introduction line 40 - is an enveloped virus with glycoproteins
Answer: Correction has been made.
5. Introduction line 49 "to deal with" also too vernacular, reword
Answer: The line has been reworded.
6. Apoptosis line 69, only certain viruses (naked) would benefit from apoptosis in order to release virions, right? Enveloped viruses in certain cases do not want apoptosis to occur due to the necessary production of membranes? This could be clarified.
Answer: We agree with the reviewer’s point. The word enveloped has been added.
7. ORF3a - is it know how Orf3a induces apoptosis? If not, then this should be stated directly.
Answer: ORF3a induces caspase-8 dependent intrinsic apoptosis. The mechanism has been explained in the lines 139-141.
8. ORF6 line 139 "the" membrane
Answer: Correction has been made.
9. ORF 8 line 156 - IFN-beta correct?
Answer: Yes INF-β has been used for IFN-beta, since it is prevalently used in the literature.
Reviewer 2 Report
This short review summarizes the current research about SARS-CoV-2-associated apoptosis, which may contribute to COVID-19 pathogenesis; a clear and concise review article.
Author Response
We thank the reviewer for the appreciation.
Reviewer 3 Report
Programmed Cell Death in SARS-CoV-2 Infection: A Short Review
This review by Deshpande and his group aims to summarize the programmed cell death mechanism of SARS-CoV-2 infection. They discussed the ORF family and introduced the family members in detail. They also described the apoptosis mechanism of pulmonary epithelial cells. Moreover, they listed several potential signaling transduction and downstream targets in this model. To improve the quality of this review, I have listed some suggestions and comments:
Major comments:
- Although the authors described TNF-R1 and FAS/CD95 as the two most important members of the extrinsic pathway. However, they should explain the reasons in detail and make this conclusion based on the evidence. In addition, which component is considered the minor factor in this model?
- They introduced the ORFs family consisting of 3a, 3b, 6, 7a, 7b, 8, 9b and 10. But they did not describe the function and expression of ORF3b, 7b, 9b and 10.
- What is the difference between ORF8L and ORF8S and their full names?
- They can expand their description and distinguish these events into SARS-CoV, MERS-CoV and SARS-CoV-2.
- The figure should be reorganized and they did not indicate that some components may translocate their locations.
Minor comments:
1. Lines 40-42 should add the reference.
2. Lines 47-53 should add the reference.
3. Lines 89-100 should add the reference.
4. Lines 114-122 should add the reference.
5. Line 152 should add the reference.
6. Line 156 should add the reference.
Author Response
Major comments:
- Although the authors described TNF-R1 and FAS/CD95 as the two most important members of the extrinsic pathway. However, they should explain the reasons in detail and make this conclusion based on the evidence. In addition, which component is considered the minor factor in this model?
Answer: We have modified the sentence to state “two important members of the extrinsic pathway” instead of “two most important members of the extrinsic pathway”. As explained in the proceeding line TNF-R1 and FAS/CD95 interact with receptors and help recruit Fas-associated death domain protein (FADD) as well as pro-caspase 8, for assembling death-inducing signaling complex (DISC), which in turn helps in the cleavage of caspas-8. We have added TNF-R1 in that line which was not there before. A line explaining the role of DR4/DR5 and TRAIL has also been added.
- They introduced the ORFs family consisting of 3a, 3b, 6, 7a, 7b, 8, 9b and 10. But they did not describe the function and expression of ORF3b, 7b, 9b and 10.
Answer: The function of ORF 3b, 7b, 9b and 10 is still unknown in the context of SARS-CoV-2 and lung epithelial cell death. Although literature is evolving, studies have not yet fully explained the functions of these remaining ORF proteins, hence could not be included in the review.
- What is the difference between ORF8L and ORF8S and their full names?
Answer: The full names of ORF8L and ORF8S have been added and the difference has been explained. Relevant reference has also been cited.
- They can expand their description and distinguish these events into SARS-CoV, MERS-CoV and SARS-CoV-2.
Answer: As the focus of the review as suggested in the title as well as the abstract, is the programmed cell death caused due to SARS-CoV-2, SARS-CoV and MERS-CoV have been mentioned only in the introduction to explain the evolution of the virus and not in the context of the programmed cell death.
- The figure should be reorganized and they did not indicate that some components may translocate their locations.
Answer: The figure has been improved and reorganized and the figure description has been revised to include the point that ORF6, ORF7a and NSP6 are located at the membrane and ORF6 can translocate to lysosomes and autophagosomes.
Minor comments:
- Lines 40-42 should add the reference.
Answer: Reference has been added.
- Lines 47-53 should add the reference.
Answer: Reference has been added.
- Lines 89-100 should add the reference.
Answer: References have been added.
- Lines 114-122 should add the reference.
Answer: Reference has been added.
- Line 152 should add the reference.
Answer: Reference has been added.
- Line 156 should add the reference.
Answer: Reference has been added.
Reviewer 4 Report
The brief review by Deshpande and Zou is informative and useful for the scientific community to understand the programmed cell death in SARS-CoV-2 infection. I recommend this manuscript for acceptance after a minor revision for the following typos.
Line 9: Keep the font case of the abbreviation SARS-Cov-2 consistent. It has been mentioned as SARS-Cov-2, SARS-CoV-2, and SARS-COV-2 in the manuscript. Correct.
Line 15: Delete ‘an’
Line 29: Mention the date of collection of the statistics.
Line 31: Italicize the family ‘Coronaviridae’.
Line 32: Define the abbreviations ‘HKU1, NL63, OC43, 229E, SARS-CoV, MERS-CoV’ at their first mention.
Figure 1: I would recommend improving the quality of the figure.
Author Response
Line 9: Keep the font case of the abbreviation SARS-Cov-2 consistent. It has been mentioned as SARS-Cov-2, SARS-CoV-2, and SARS-COV-2 in the manuscript. Correct.
Answer: All the abbreviations have been unified as “SARS-CoV-2”.
Line 15: Delete ‘an’
Answer: The correction has been incorporated.
Line 29: Mention the date of collection of the statistics.
Answer: The statistic has been updated to the current date and the date has been added in parantheses.
Line 31: Italicize the family ‘Coronaviridae’.
Answer: The word has been italicized.
Line 32: Define the abbreviations ‘HKU1, NL63, OC43, 229E, SARS-CoV, MERS-CoV’ at their first mention.
Answer: The descriptions of the abbreviations have been added.
Figure 1: I would recommend improving the quality of the figure.
Answer: The figure has been improved and reorganized.
Round 2
Reviewer 3 Report
I have no further questions and concerns.
