Nipah Virus Encephalitis: Pathogenetic Aspects and Current Therapeutic Strategies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 The review focuses on two main aspects: the mechanisms underlying NiV pathogenesis and the current landscape of therapeutic and preventive strategies. 

Overall, the manuscript is well written, clearly structured, and adequately referenced. It provides a comprehensive overview of Nipah virus (NiV), covering key aspects of viral biology, epidemiology, and pathogenic mechanisms, while also summarizing current advances in therapeutic and vaccine development. The authors draw on a substantial body of relevant literature, including both recent studies and well-established references in the field. The title and abstract are consistent with the content of the manuscript and accurately reflect the scope of the review. The sections addressing NiV pathogenicity, as well as therapeutic and vaccine strategies, are particularly clear and well organized. 

The topic is timely and highly relevant in the current global health context. The increasing emergence of infectious agents with epidemic or pandemic potential, together with their significant societal impact, underscores the importance of studies addressing high-risk zoonotic pathogens. In the post-COVID-19 era, emerging viruses such as NiV remain a major public health concern, reinforcing the value of comprehensive reviews that synthesize current knowledge and identify priorities for future research. 

The comments provided below are intended to further improve the clarity, organization, and consistency of the manuscript. 

 

Minor Issues 

1. Writing and formatting errors 

Line 18 – A word appears to be missing at the beginning of the sentence starting with “Nipah virus (NiV)”. 

Line 65 – The word “Pteropus” appears to be incorrectly formatted. 

Line 492 – Please verify whether reference 98 is correctly associated with this statement. The “?” symbol should be removed. 

Line 843 – Some references are cited using the symbol “–”. Please verify and standardize the citation format throughout the manuscript. 

1. Suggestions 

Line 405 – The subsections “G protein”, “F protein”, and “Cellular Receptors” could be formatted as 6.2.1, 6.2.2, and 6.2.3, respectively, for consistency with the numbering system used later in the manuscript (e.g., in the Therapies section). Please verify whether all subsection headings follow a consistent numbering format throughout the manuscript. Some sections appear to deviate slightly from the numbering scheme used in other parts of the text. 

Line 474 – It is unclear whether the authors are referring specifically to infection of the central nervous system (CNS) or only to the brain. If the discussion includes other CNS structures (e.g., spinal cord), the section title should be adjusted accordingly to refer to CNS infection rather than brain infection. It would be helpful to clarify whether the infection is restricted to the brain or whether other CNS structures.  

Line 491 – The spelling of oedema/edema should be standardized throughout the manuscript.  

Line 591 – The subsection “Clinical and Pathophysiological Considerations” appears to be related to the neutralizing antibodies discussed in section 7.1. It may be more appropriate to include this subsection under section 7.1.3. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review article “ Nipah Virus Encephalitis: Pathogenetic Aspects and Current Therapeutic Strategies” provides a comprehensive overview of Nipah virus epidemiology, disease transmission, replication cycle, current therapies, and vaccine development. The authors have made a commendable effort to consolidate the available literature. I would suggest a few additional refinements to make the article more streamlined and engaging for readers.

Major concerns
(1) Figure 1: This figure is very thought-provoking and will certainly enhance the reader’s interest. However, I was thinking about how this tree could be presented in a more informative way—particularly to highlight how the order Mononegavirales includes several highly pathogenic members. It would be helpful to briefly introduce the order Mononegavirales first, then move to Henipavirus, and finally to Nipah virus. The figure legend can remain concise, but a more detailed description should be included in the main text. Also, it is unclear why a few virus names are boxed. Perhaps you could instead indicate high pathogenicity directly within the phylogenetic tree itself.

(2) Please include a table summarizing the major Nipah virus outbreaks along with the corresponding references.

(3) Figure 4: Currently, the figure appears messy and is difficult to interpret. Please rework it to clearly illustrate disease transmission, the major organs affected, and disease manifestations in the tissues, including the key readouts. Make it more scientific.

(4) Sections 5 and 6: This section requires significant revision and reorganization:

(a) Merging Sections 5 and 6: These sections could be combined and presented more systematically. Describe how infection occurs initially, its clinical presentation, progression to systemic dissemination, and finally organ-specific involvement with corresponding manifestations.

(b) Figure 4: Currently, the figure is messy and difficult to interpret. Please rework it to clearly illustrate disease transmission, major organs affected, and disease manifestations in the tissues, including key readouts. Ensure that Figure 4 aligns with the revised structure suggested in (4a) and presents the information in a scientific and coherent manner.

(c) Section 6.2: This section should be moved to Section 3, where the replication cycle is described, so that it appears upfront in the logical flow.

(d) Sections 6.4 to 6.7: These can be grouped under a broader heading, such as “Nipah Encephalitis” or “Infection in the Brain”. Describe how the virus enters the brain, its interactions within different neural cell types, and the immune mechanisms involved.

(5) Immune Mechanisms: Create a separate section detailing innate immune mechanisms, including RNA sensors involved in Nipah infection and other pattern recognition receptors (PRRs). Incorporate the entirety of Section 6.3 on immune evasion here. This section is likely to attract the most interest from readers, so please also provide your perspective on how immune evasion may occur through additional mechanisms and any host directed therapy you could arrive at.

(7) Section 7: This section would benefit from a tabular presentation of current therapies, indicating the stage of infection at which each therapy can be administered. If possible, include data on success rates to make the table more informative and impactful. The table can merge with current vaccine developments too.

(8) Include a section where you talk about disease risk and management. Try to adapt a perspective on "Kerala model" as the public health management to reduce the risk is highly commendable. Make readers aware of this. 

Minor concerns

(i) Abstract – I would like to see the abstract written in a more concise and better-rearranged manner and better reflected in your perspective. I would also like to see your perspective on disease management. The sentence “This review synthesizes …” should be the last sentence of the abstract. Additionally, the first word “Nipah” is missing.

Figure 3: This figure should be prepared by the authors themselves. There is no need to adapt it from other sources.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The revised version has improved and looks great, though the figures need a professional look.

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf