Autophagy in Virus Infection: A Race between Host Immune Response and Viral Antagonism

Round 1

Reviewer 1 Report

Autophagy is a cellular degradation process that is critical maintenance of cellular homeostasis. Nutrients unavailability or low energy or cellular stress factors induce autophagy. Viruses have co-evolved with its host and have the ability to manipulate host's cellular machinery. Virus can modulate autophagy pathway. But autophagy is a double edged sword, it serves an antiviral immune response in some virus infections like HCV. But autophagy can also a pro-viral cellular response like HPIV3. This is discussed well in the review. The arms race between virus and host in the context of autophagy has been discussed well in this review. It is a well written and very structured review.

I have one minor suggestion

1. In the abstract they mention “we leave with the thought that autophagy can be targeted for therapeutic interventions”. I would suggest to have a small section at the end and discuss a couple of examples.  

Author Response

“Autophagy is a cellular degradation process that is critical maintenance of cellular homeostasis. Nutrients unavailability or low energy or cellular stress factors induce autophagy. Viruses have co-evolved with its host and have the ability to manipulate host's cellular machinery. Virus can modulate autophagy pathway. But autophagy is a double edged sword, it serves an antiviral immune response in some virus infections like HCV. But autophagy can also a pro-viral cellular response like HPIV3. This is discussed well in the review. The arms race between virus and host in the context of autophagy has been discussed well in this review. It is a well written and very structured review.”

Thank you for your positive comments.

“I have one minor suggestion

1. In the abstract they mention “we leave with the thought that autophagy can be targeted for therapeutic interventions”. I would suggest to have a small section at the end and discuss a couple of examples.”

We have added a new section (#7) to address this.

Reviewer 2 Report

Specific comments:

The authors described the regulatory function of autophagy in viral infections, there are many key points need to be further improved.

1. The whole structure of the paper does not make sense, like the “Autophagy as an anti-viral immune response” was described earlier, then the fifth point “Autophagy and the interferon system” was discussed separately. I would suggest the authors put the interferon staff under the innate immunity topic, and put adaptive and innate parts under the subject of “Autophagy as an anti-viral immune response”, then discussed each section separately.
2. The types of autophagy are not complete, so authors should read more papers about virus-induced autophagy carefully and provide more details about each type of autophagy in infections, and provide a detailed figure for each one in the review which would help readers to understand the mechanism of different autophagic-pathway and their specific functions in different infections.
3. Also, why did the authors choose those viruses and viral proteins for critical discussion? How about other viruses excluded in this review?

Author Response

“The authors described the regulatory function of autophagy in viral infections, there are many key points need to be further improved.”

Thank you!

1. “The whole structure of the paper does not make sense, like the “Autophagy as an anti-viral immune response” was described earlier, then the fifth point “Autophagy and the interferon system” was discussed separately. I would suggest the authors put the interferon staff under the innate immunity topic, and put adaptive and innate parts under the subject of “Autophagy as an anti-viral immune response”, then discussed each section separately.”

Thank you, we have now reorganized based on this suggestion.

2. “The types of autophagy are not complete, so authors should read more papers about virus-induced autophagy carefully and provide more details about each type of autophagy in infections, and provide a detailed figure for each one in the review which would help readers to understand the mechanism of different autophagic-pathway and their specific functions in different infections.”

Thank you for this excellent suggestion. We have now added lipophagy, macropinocytosis and virophagy. All these forms of autophagy have now also been presented in Figure 2.

3. “Also, why did the authors choose those viruses and viral proteins for critical discussion? How about other viruses excluded in this review?”

Thank you for pointing this out; we could not accommodate all the viruses and viral proteins in this article. We tried to use some viruses that are known to be involved in autophagy. However, there are many more examples, which have been covered in other reviews.  

Reviewer 3 Report

This review outlines different types of autophagy and the role of autophagy as a pro-viral and anti-viral cellular response. The review itself is well written  with each and every heading explained clearly. There are multiple reviews in the literature outlining autophagy as pro and anti-viruses detailing autophagy as an essential component of host responses. However, this review has good schematic representation of all the mechanisms.

The review can benefit from explaining the different cytokines and involvement of innate or adaptive immune system when explaining specific viruses. Overall it is well written.

Author Response

“This review outlines different types of autophagy and the role of autophagy as a pro-viral and anti-viral cellular response. The review itself is well written  with each and every heading explained clearly. There are multiple reviews in the literature outlining autophagy as pro and anti-viruses detailing autophagy as an essential component of host responses. However, this review has good schematic representation of all the mechanisms.”

Thank you for your positive comments.

“The review can benefit from explaining the different cytokines and involvement of innate or adaptive immune system when explaining specific viruses. Overall it is well written.”

Thank you for this comment; this review was intended for viral immunology readers. We have used interferon, the most widely studied anti-viral cytokine (section#4), extensively in this article. As the reviewer suggested, additional cytokines also modulate autophagy, both in viral and non-viral contexts. These topics are not within the scope of this review; a future review article will cover those topics.

Round 2

Reviewer 2 Report

The ms has been improved properly. The minor comment is about "Macropinocytosis" section, which can be deleted because it is more related to actin but definitely different from autophagy.

Author Response

Thank you for your comments; we have removed the section on macropinocytosis and revised the manuscript accordingly.