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Dear Dr. Wang and Dr. Yang,
Thank you for sending the revision back! Two reviewers have completed their reviews, and they recommend the acceptance of this manuscript. Congratulations!
Hao
[# PeerJ Staff Note - this decision was reviewed and approved by Gwyn Gould, a PeerJ Section Editor covering this Section #]
Introduction is vastly improved.
The authors have gone above and beyond to address all the previous comments. In addition to the revised text, the revised Figure 1 and the newly added Table 1 also help provide more relevant details and complement the text.
The added paragraphs in the Conclusion section clarify the current knowledge and future directions regarding behavioral immunity in C. elegans.
The manuscript has vastly improved and I am quite blown away by the improvement. This review will be a wonderful addition to the field.
no comment
I am completely satisfied with what the Authors modified according to requirements.
I believe that the Manuscript is a real value to the field of interest. I recommend for publication.
Dear Dr. Wang,
Thank you for your patience during the review process at Peer J. Your manuscript has now been reviewed by four experts, who have provided differing opinions. After careful consideration, I have decided that a major revision is necessary to address the concerns raised by the reviewers. Additionally, please ensure that the English language is thoroughly improved in your resubmission.
One of the reviewers (reviewer 4) attached the comments as a pdf file. I included that with this email just to be sure you have it.
Sincerely,
Hao Chen
One minor point that could further strengthen this review is the incorporation of more transition phrases. This would enhance the flow between sections and ideas, ultimately guiding readers more effectively through the complex information presented.
Below is the example in the introduction part.
e.g., Introduction
In most model organisms, the mechanisms underlying neuroimmune regulation are poorly understood due to the high complexity of their nervous and immune systems, and the role of the nervous system in immune regulation is often obscured by the presence of adaptive immunity. For instance, C. elegans is a simple host organism that feeds on bacteria [1, 2]. The species composition of its bacterial food significantly influences various behaviors, such as feeding, locomotion, and aerotaxis [3, 4]. Therefore, the ability to distinguish between pathogenic and non-pathogenic microbes is essential for the survival and homeostasis of the host organism. As an illustration, the bacterial pathogens P. aeruginosa PA14 may kill C. elegans in various ways, including quorum sensing, host colonization, iron-induced hypoxic response, damage to host translation, and antimicrobial response [5-7]. Interestingly, to the best of our knowledge, naive C. elegans initially exhibit an innate attraction towards the odors of PA14, and then gradually turn to escape from it [8, 9]. Consequently, for survival, C. elegans employs behavioral immunity, which refers to avoidance behaviors that protect against pathogen infections [10], as a key defense strategy. It involves both innate pathogen recognition and internal state modulation due to intestinal infection [11]. The avoidance behavior of C. elegans towards PA14 develops 12 hours after interactions between the host and pathogens [12, 13]. In particular, bloating of the intestinal lumen, induced by bacterial colonization and gut virulence factors, plays a significant role in this avoidance behavior [12].
Moreover, animals detect intestinal lumen bloating as a danger signal, then trigger defense responses, such as activating stress response pathways, inducing behavioral changes, and upregulating antimicrobial peptides [12, 14-16].
In this review, we discuss how the nervous system coordinates behavioral immunity by translating the recognition of pathogen-derived cues to physical avoidance in C. elegans. This discussion aims to provide insights for comprehensively understanding the molecular and cellular mechanisms underlying behavioral immunity and to shed light on further analysis of the role of the nervous system in regulating behavioral immunity.
The introduction effectively sets the stage by highlighting the complexity of neuroimmune regulation in most model organisms and positioning C. elegans as an advantageous model due to its simplicity. This clear framing helps readers understand why C. elegans is a suitable subject for this kind of study.
The key concepts of behavioral immunity, pathogen recognition, and the role of the nervous system are introduced clearly. The focus on the avoidance behavior of C. elegans and its modulation by neuroimmune pathways is well-articulated.
This review highlights the advantages of using C. elegans as a model organism. The introduction to the research review on behavioral immunity in C. elegans outlines how the nervous system guides this process through pathogen detection, aversive olfactory learning, and motor output generation. Key points include the roles of chemosensory neurons in detecting pathogen-derived cues and damage-associated molecular patterns (PAMPs and DAMPs), the involvement of aversive olfactory learning in immune responses, and the complex neuroendocrine pathways driving motor behaviors in response to infection. The text emphasizes the intricate connections between neural circuits and immune responses, highlighting the importance of these interactions for survival and homeostasis in C. elegans.
Clearly defines the research topic (behavioral immunity in C. elegans) and its significance.
Highlights the advantages of using C. elegans as a model organism.
Provides a solid background on C. elegans' interaction with P. aeruginosa.
Explains the concept of behavioral immunity and its development in C. elegans.
States the review's objective: understanding the role of the nervous system in behavioral immunity.
Overall, this review provides a strong foundation for the research review.
No Comments
No Comment
No Comment
Line 38: Please italicize "P. aeruginosa"
Line 38: quorum sensing itself it not responsible for the killing of C. elegans. From the works the authors cite, it shares regulators with pathogenic factors but is not the key component to killing. Please rewrite this section.
Line 40: The authors do not make it clear how "antimicrobial response" kills C. elegans during P. aeruginosa infection. Please add more citations to support this claim.
Line 94: Please italicize "Serratia marcescens"
Line 195: Please italicize "ins-11"
Review is appropriate and timely, since the last review focused on immune behavior of C. elegans was in 2020 by Singh and Aballay. Since then there has been a number of publications, of which most are cited in the manuscript.
The introduction goes too specifically into examples from PA14. I think it can be kept more general, since most of the descriptions about immune behavior applies to other pathogens as well. Also, more can be said of the significance and importance of studying behavioral immunity in C. elegans, and how this may contribute to our general understanding of immune behaviors in other organisms. This will make the review relevant to a wider audience.
Although the review is timely and cites a wide range of studies, the material needs to be organized in a more coherent logic. This will require a substantial overhaul of the manuscript and much of it will need to be rewritten.
1. Subheadings:
Currently the headings proceed as: (3.1) pathogen-derived cue – (3.2) olfactory learning – (3.3) motor outputs, but the literature discussed cannot be easily grouped into these topics. As a result, items discussed under each headings seem to overlap and bleed into different topics. Moreover, some paragraphs don’t fit into any of the three topics, so they seem like they were placed in arbitrary parts of the manuscript (especially line 262-273). The authors can either create a completely different set of subheadings, or stay with the current ones but organize the material better to fit into each topic. For example, one way would be to divide the literature into different signaling pathways, such as monoamine signaling, TGFbeta, p38 MAPK, insulin-like signaling, glutamatergic/cholinergic, and so on. How neuronal signals are processed, from pathogen-derived cue to learning to motor output, can be summarized in a paragraph in the beginning to lay the context for the subsequent discussion of the different pathways. This is just one suggestion.
2. Paragraph structure:
Because of the poor organization, each paragraph is a mere numeration of various pathways and neurons listed one after another. For example in section 3.1.1 starting in line 81, after the opening sentence, the authors go straight into phenazine-1-carboxamide and pyochelin, then the neuron ASJ, and DAF-7, and aerotaxis. Then the authors moves on to 1-undecene, and that it's sensed by AWB. Then serrawettin W2, AWB. Then dodecanoic acid, detected by the SRB-6 receptor. There is no general overview that ties all these disparate information together other than the fact that they all deal with sensing external cues. Because each information is listed like this, there is no time to go into each of the specifics, such as what DAF-7 is (TGFbeta, conserved in most organisms), what AWB is (one of the chemosensory neurons that mediate sensing of aversive volatile chemicals).
3. Some of the information can be organized into a table, so that the text of the review can focus more on the overall mechanism that is shared by all the specific examples as well as relevant details and background needed to understand them.
4. There are also some jargons and terms adopted straight from the cited primary literature without any context or explanation. A few examples include “steering trajectory deviation” in line 251, “four-layer aversive learning circuit” in line 147. “Aerotaxis” is mentioned in line 90, but the word is thrown out without any context or explanation. How that is relevant to immune behavior is only mentioned two paragraphs down.
5. Discussion of recent findings: it is important that the review include discussion of recent findings that are not included in previous reviews. The manuscript does cite many of them, but findings from those papers are sometimes not properly discussed. For example, study by Morud et al. (ref #46) that is cited in line 156, identifies a previously unknown serotonin-gated ion channel that is required for learned avoidance to PA14. However, the authors only mention MOD-1 (ref #8), and cite both papers as if both papers were about MOD-1-mediated aversive learning, and never mention any findings from ref #46.
6. The manuscript talks about PAMP, but C. elegans immunity doesn't involve what we traditionally consider as PAMP recognized by Toll-like receptors. If the authors choose to use the word PAMP to describe any compounds emitted by pathogens, they should make that clear and define the word.
Due to the poor writing, it is very hard to follow all the facts listed.
As for the conclusion, sentences are too general and vague and doesn’t contribute to any big-picture insight or significance. Because the manuscript fails to put all the relevant research into a bigger picture context, it is not possible to identify any direction or unresolved questions.
English writing needs to be substantially improved.
no comment
The authors have the outstanding aim to collect existing knowledge on pathogen-elicited behavioral patterns, mainly focusing innate aversion and aversive associative memory. The search criteria in the literature is clear and adequate, however, it lacks important keywords, which caused gaps in the collection of essential papers. Although the overview of the scoped phenotype is satisfying, definitions need to be clarified.
Strength of the study is the thorough and elegantly limited collection of neuronal circuits, which is a novelty in my opinion. The goals do not meet the Discussions, some phenomena, definitions and references are employed wrongly, which are suggested to be fixed.
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