Immune-Mediated Pathogenesis in Dengue Virus Infection
Round 1
Reviewer 1 Report
The manuscript under the title "Immune-Mediated Pathogenesis in Dengue Virus Infection" submitted by Arshi Khanum et.al., is related to the highly concerning disease of the present era. This manuscript is written very well and had covered all aspects of Immunology. However, If the authors add section of ISGs and viral interaction it will grab a broad readership. The manuscript is in good form and balanced review of the available literature.
Author Response
The manuscript under the title "Immune-Mediated Pathogenesis in Dengue Virus Infection" submitted by Arshi Khanam et.al., is related to the highly concerning disease of the present era. This manuscript is written very well and had covered all aspects of Immunology. However, If the authors add section of ISGs and viral interaction it will grab a broad readership. The manuscript is in good form and balanced review of the available literature.
REPLY: Thank you for this great suggestion. As per the reviewer’s suggestion, we have included a section on the role of interferon stimulated genes (ISGs) and viral interaction during dengue infection under newly added Section 7 (pages 13-14, Lines 447-497).
Reviewer 2 Report
I have reviewed in detail the review entitled: “Immune-Mediated Pathogenesis in Dengue Virus Infection”. This interesting review includes the most recent research on the different mechanisms that the dengue virus uses to evade the immune system response. I consider that the authors conducted an excellent review of the literature on dengue and the immune system. The introduction seems adequate and sufficient. The subtopics are coherent and in a logical order. The figures are impeccable and very well made. Overall, I find this review to be well-written.
I consider that the review covers some aspects previously addressed by other authors, such as the cytokine storm, the cellular response, etc. However, they do mention a piece of recent research related to cellular exosomes. In this part, they describe the mechanism that the Dengue virus uses to be able to continue with the infection through exosomes. Moreover, I consider that the authors used the references of the works well. Finally, I consider that the figures are correct, and that it might be necessary to include a table that would describe, as a summary, the cells, cytokines and mechanisms involved in the pathogenesis of DENGUE.
Author Response
REPLY: We appreciate the reviewer’s comments and recommendations. However, we believe that we have discussed about the cells, cytokines, and mechanisms involved in the pathogenesis of dengue infection are both in detail within the text and summarized in the four figures included. With these four figures, we decided not to create a table as we thought it would be redundant. Nevertheless, if the reviewer still suggests that we should include a table, we would be happy to create one.
Reviewer 3 Report
In this review, the author summarizes the host immune response critically involved in the pathogenesis of DENV infection. The severity of dengue virus infection depends on many immunopathogenic mechanisms involving both viral and host factors. This is a well-written review describing involvement of T-cell response, Antibody-Dependent Enhancement (ADE), exosomes and cytokine production in primary and secondary dengue virus infection. It is clearly a big, concerted effort and well written review, which sheds a new light on all the immune response contribute to disease progression. Despite of all positive outcomes of the review, I found several points, where it can be improved.
Comments –
1. Manuscript describing role of immunological factors in severe primary and secondary DENV infection. Secondary heterologous DENV infection leads to the development of non-protective environment, resulting in a severe dengue disease by excessive production of cytokine. In whole paper, author is talking about immunological factors involving in severe primary and secondary infection. If author can show, different serotype relation with these immunological factors or author can make an extra paragraph, describing immunological factors related to four different serotypes during severe primary and secondary infection, that will be a great addition to this review.
2. In line 95, 96 and 97, Author did not add reference. “The virus-antibody complex is then phagocytosed by the cells via crystallizable fragment-γ (Fcγ) receptors and results in increased viremia and pathology.’ Please add reference.
3. Figure 1 is not clear, it is blurry. Please make it clear.
4. In Figure 2, Author describes about extrinsic and intrinsic Antibody-Dependent Enhancement (ADE) in dengue virus infection. Font size is very small in downregulation of TLP signaling, its not visible. Please make it clear, so that it will be easily understandable to the readers.
5. In line 376 and 377, et al should be in italic form.
Comments for author File: 
Comments.pdf
Author Response
- Manuscript describing role of immunological factors in severe primary and secondary DENV infection. Secondary heterologous DENV infection leads to the development of non-protective environment, resulting in a severe dengue disease by excessive production of cytokine. In whole paper, author is talking about immunological factors involving in severe primary and secondary infection. If author can show, different serotype relation with these immunological factors or author can make an extra paragraph, describing immunological factors related to four different serotypes during severe primary and secondary infection, that will be a great addition to this review.
REPLY: We appreciate the reviewer for the insightful comment. We have included a section on the different serotype relation with immunological factors and its association with disease outcome in dengue infection on page number 17 (lines 538-572).
- In line 95, 96 and 97, Author did not add reference. “The virus-antibody complex is then phagocytosed by the cells via crystallizable fragment-γ (Fcγ) receptors and results in increased viremia and pathology.’ Please add reference.
REPLY: As per the reviewer’s suggestion, we have added the reference mentioned.
- Figure 1 is not clear, it is blurry. Please make it clear.
REPLY: We have updated Figure 1 with a higher resolution image. Note that part of Figure 1C illustration has been intentionally blurred to depict mechanism that is unknown.
- In Figure 2, Author describes about extrinsic and intrinsic Antibody-Dependent Enhancement (ADE) in dengue virus infection. Font size is very small in downregulation of TLP signaling, it’s not visible. Please make it clear, so that it will be easily understandable to the readers.
REPLY: We have updated the Figure 2 to have the TLR pathway clearer and with higher resolution.
- In line 376 and 377, et al should be in italic form.
REPLY: We have italicized et al in the text.
