-->PPATHOGENS-D-25-02784

Hidden hematological, biochemical and immune costs of asymptomatic malaria infections in semi-wild chimpanzees

PLOS Pathogens

Dear Dr. Rougeron,

Thank you for submitting your manuscript to PLOS Pathogens. After careful consideration, we feel that it has merit but does not fully meet PLOS Pathogens's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

James G. Beeson, MBBS, PhD

Academic Editor

PLOS Pathogens

Margaret Phillips

Section Editor

PLOS Pathogens

-->-->Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

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Additional Editor Comments:

The two reviewers have provided many helpful and thoughtful comments and suggestions for improvement of your manuscript. Please address all the reviewers comments as best you can, and you can contact me if you have any concerns or queries.

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Reviewers' Comments:

Reviewer's Responses to Questions

Part I - Summary

Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship.

Reviewer #1: The study by Nowakowski highlights very important and interesting points, as great apes can be infected by malaria parasites, including some species similar to those that infect humans, if I understood correctly. A better understanding of malaria infection in great apes, as demonstrated in the work presented here, is essential to achieving the ultimate goal of eradicating malaria. However, the presentation of the study requires greater rigor, specifically regarding the Luminex data and the statistical tests used. Currently, the methods section lacks sufficient information to allow for reproducibility of the study. I advise the authors to assess the distribution of their data to determine whether the use of parametric tests is appropriate. If this analysis has already been performed, the information should be included in the methods. Regarding the Luminex data, it is unclear which samples were used in each of the two different Luminex kits, and which reported data are from plasma samples versus PBMC-stimulated supernatants. Clarifications on these points will greatly strengthen the manuscript.

Reviewer #2: The authors present an excellent piece of work representing a unique opportunity to rigorously assess Plasmodium infection in chimpanzees. The conclusions are generally well aligned with the data, and the work is very nearly complete. The authors should be commended on an ambitious and fascinating project. There are a couple deficits which should be corrected to enable full realization of the work including: 1) clarifying true negativity in the uninfected group and; 2) drawing clearer comparisons to human infections in terms of age distribution and acquisition of asymptomatic infection.

**********

Part II – Major Issues: Key Experiments Required for Acceptance

Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions.

Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject".

Reviewer #1: Major issues:

- The Luminex assays are not clear. You mention 2 kits (one from Invitrogen and one from BioTechne), are they different? If yes, do you mean that you use one kit for the plasma sample and the other one for the supernatant of the in vitro stimulation assay? Can you please give the proper reference to these kits? As of now, using only the name you cited is not enough to find a kit. Did you compare data generated from these 2 kits? How did you correct for possible batch effect? In the manuscript, sometimes you mentioned MFI and sometimes quantitative data. Can you please expand on how the data from these 2 kits were analyze and if any quantitative analysis were performed, how you did. Also, how much volume did you use? at which dilutions? Singlet or duplicate? Luminex kits usually use different dilution of the plasma versus the supernatants. As of now, we do not know where the data shown in the figures are coming from (plasma vs supernatant). It is crucial to better indicate which analysis you did using the plasma data versus the supernatants from the PMA/Iono stimulations of the PBMCs as is can mislead the interpretation.

- Welch’s test is a parametric test. Did you assess the distribution of the data prior selecting parametric test? If not, you should assess the distribution of your data prior selecting a test. Data that are not following a normal distribution should use a non-parametric test. I will suggest to the authors to review all their data distribution and tests. Line 517-519: What do you mean by “standardized using z-scores”? what did you standardized exactly? Please add details.

Reviewer #2: 1. Can the authors include qPCR data for the nanopore-negative samples as well? This will not only help ensure accuracy of the nanopore, but strengthen arguments about asymptomatic infection.

2. For the blood parameters in Tables 1 and 2 as well as Figure 3, could the authors provide some context of normal ranges. I understand these may be speculative for chimpanzees, but rough reference values should be available. This will help interpret what, if any, of these deviations are clinically significant.

3. The effect of age is a very interesting and important finding, yet needs to be more concrete. Since there is only a single animal under ~7 years of age, this should be a major caveat discussed considering that the heaviest burden of infection and disease in humans occurs in the first few years of life. Secondly, to claim that the older animals are uninfected, qPCR would be needed.

4. The unpublished longitudinal data mentioned in the Discussion should either be presented to add context or removed.

5. Non-human primates, at least those in captive colonies, mask symptoms and pain extremely well especially in the presence of humans. Considering this and that animals were sedated during collection, discussion of “asymptomatic” infection needs to be adjusted and supported by more data. In humans, symptomatic malaria includes positivity (often by smear) and fever, chills, etc. Obviously, symptoms outside of fever are impossible to assess. Therefore, it would be more useful if temperature is included (if measured) and the discussion centered around comparisons of objective values obtained from blood paramaters to not just normal ranges but also those seen for malaria infections in human across the ages (from symptomatic children to asymptomatic adults). This is done to some extent for the inflammatory cytokines, but more context via comparisons to healthy and unhealthy values would greatly improve interpretability.

**********

Part III – Minor Issues: Editorial and Data Presentation Modifications

Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity.

Reviewer #1: Introduction:

- Are these plasmodium species carried by the same vector than the one infecting human?

- Do you consider the great apes as potential reservoir for malaria?

- Did you find similar species in the Plasmodium infecting Great Apes and Human in Gabon?

Methods:

- For how many individuals the CBC was unavailable?

- PBMCs stimulation section: how many cells did you stimulate per individuals? And in which final volume of culture media? This information matters as you are using the supernatant to assess the cytokines/chemokines. Adding these details will allow the reproducibility of your data.

- Line 501-502: cytokines/chemokines were assessed from the plasma sample and the supernatants of the stimulated PBMCs. Please correct as of now it sounds that you tested plasma from stimulated PBMCs which is not what it is.

- Data availability: you should consider sharing your Luminex and other data through the ImmPort portal.

Results:

- It is not clear how many chimpanzees were infected versus non-infected and how this determination was made: qPCR results only? Or did you include other parameters such as anemia, fever?

- The tables will benefit to have the age (median/IQR) for each compared set of groups as it seems from the figure 1B that most of the non-infected are older than the infected ones.

- Did you correct by age for the analysis as it seems to be a cofounding factor?

- It will help to know the number of individuals for each group (PG/PR, PO, …), the only information is 1 individual with Po.

- Figure 3, it is not clear if the cytokines/chemokines data are coming from the plasma or from the supernatants of the PBMCs in vitro stimulation assay. Did the authors compare the levels of cytokines/chemokines between the plasma of infected and non-infected individuals, but also between the plasma and supernatants for each group? Because PMA/Ionomycin is a “hammer: triggering high levels of cytokines responses it is not malaria specific. However, comparing the data from the plasma versus the in vitro assay will allow to better be found correlation between the cytokines that are specifically induced during malaria infections.

- Missing Y-axis on all the figure 3

- Figure 4C, what means “value” in the Y-axis?

- The figures will benefit to have the statistical test outcomes indicated.

Discussion:

- Line 246: You mentioned that having more malaria infection in youngling vs adults in chimpanzees’ contrast with human malaria. However, in human, malaria (symptomatic and asymptomatic) is found more frequently in children living in high malaria transmission area compared to the adults. I am not sure I am getting your point. Can you develop your thoughts?

- Line 289: It is complicated to make a point with “unpublished data” or “data not shown”. Is it possible to add a figure with this data?

- In your interpretation of the cytokines/chemokines, please indicate where these data come from, the plasma or the stimulated PBMCs, as they are not bringing the same type of information which can mislead the interpretation.

Supplementary:

- Supplementary table 1: why there are only the results for 13 individuals? Were they 13 individuals infected with malaria and 14 individuals non-infected (total of 27 individuals)? They are no individuals’ names followed by an asterisk; does it mean that none of them were infected with P. vivax-like? Is it based on this assay that you categorized your “infected” vs “non-infected group”? If so, please add a section about it in the methods.

- Supplementary table 2: Please indicate if you assessed the distribution of your data to justify the use of the t-test (which one did you used?). The table will benefit of having the median (IQR) values to show the distribution of the data that the t-test compare. Which test did you use for the categorical data such as sex and blood type?

- Supplementary figures 2, 3, 4, and 5: “value” is not an acceptable Y-axis label, you have the proper labels in the figure legends, please add them on each figure plot. Please add the statistical test on each plot if the p-value is significant. As of now, we don’t know how to interpret these results.

- For the supplemental figures 3 and 5, please indicate if the data are coming from the plasma or from the supernatant of the in vitro stimulation assay.

- Supplemental figure legend 1 and 3: What do you mean by “values are normalized residuals; negatives indicate below-average levels”? (line 47-48), please indicate any transformation of the data in the methods and/or figure legends.

- Supplemental figure legend 2 and 4: Please differentiate data coming from the plasma and the ones coming from the supernatant of the in vitro stimulation. I do not understand “values are normalized residuals; negatives indicate below-average levels” in this section. Luminex kit outcomes from cytokines/chemokines kits are quantitative based on the standards provided by the kit. Here you mention MFI instead of the analyzed data from the standard curve. Did you have issues with your standards? Even using the MFI data, what do you mean by “values are normalized residuals; negatives indicate below-average levels”? What did you do to the data to transform them? It is highly unclear.

Reviewer #2: 1. The results section should begin with a more clear description of the sampled animals akin to a cross-sectional study of humans that includes not just age range and sex, but also living conditions and prevalence of malaria in surrounding areas.

2. The breakdown of infections in each site is important for Figure 1

3. Line 168: When comparing 2/3 groups, and 2/2 groups with more than one data point, it doesn’t make sense to say the mixed infections are different than the one monoinfection.

4. Line 189 phrase “emphasized some less clear species-specific patterns.” Doesn’t make sense

5. Please add stats in Figure 3

**********

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Reviewer #1: Yes:  Catherine S. Forconi

Reviewer #2: Yes:  Brandon K. Wilder

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PPATHOGENS-D-25-02784R1

Hidden hematological, biochemical and immune costs of asymptomatic malaria infections in semi-wild chimpanzees

PLOS Pathogens

Dear Dr. Rougeron,

Thank you for submitting your manuscript to PLOS Pathogens. After careful consideration, we believe your paper is now very close to being accepted, pending some final minor revisions. Therefore, we invite you to submit a revised version of the manuscript that addresses the final minor points raised during the review process.

Please submit your revised manuscript by Jul 14 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plospathogens@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/ppathogens/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

James G. Beeson, MBBS, PhD

Academic Editor

PLOS Pathogens

Margaret Phillips

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

Additional Editor Comments:

Thank you for addressing the reviewers comments. Please address the final minor revisions requested from reviewer 2.

After you have completed this, I believe your paper will be ready to progress to formal acceptance.

Reviewers' Comments:

Reviewer's Responses to Questions

Part I - Summary

Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship.

Reviewer #1: All comments have been addressed. The conclusions are well supported by the results of this study. The methods are now clear and reproducible.

Reviewer #2: Thank you to the reviewers for taking the time to significantly edit their manuscript. The work remains as important and is now presented more clearly.

**********

Part II – Major Issues: Key Experiments Required for Acceptance

Please use this section to detail the key new experiments or modifications of existing experiments that should be absolutely required to validate study conclusions.

Generally, there should be no more than 3 such required experiments or major modifications for a "Major Revision" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend "Reject".

Reviewer #1: (No Response)

Reviewer #2: None.

**********

Part III – Minor Issues: Editorial and Data Presentation Modifications

Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity.

Reviewer #1: (No Response)

Reviewer #2: The statements about higher parasitemia in younger animals should likely be removed or significantly restated given the lack of statstics in Fig. 1B and lack of correlation in Fig. 1D. As it stands, the data could be summarized as “we did not not observe a significant correlation between age and parasitemia. However, this should be interpreted with caution only two animals were <7 years old, only one of which was infected.” If discussed, it should be placed within context of human where the primary burden of acute and chronic infection is in school-aged children and infants.

**********

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Reviewer #1: Yes:  Catherine S. Forconi

Reviewer #2: Yes:  Brandon Wilder

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To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Rougeron,

We are pleased to inform you that your manuscript 'Hidden hematological, biochemical and immune costs of asymptomatic malaria infections in semi-wild chimpanzees' has been provisionally accepted for publication in PLOS Pathogens.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens.

Best regards,

James G. Beeson, MBBS, PhD

Academic Editor

PLOS Pathogens

Margaret Phillips

Section Editor

PLOS Pathogens

Sumita Bhaduri-McIntosh

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0003-2946-9497

Michael Malim

Editor-in-Chief

PLOS Pathogens

orcid.org/0000-0002-7699-2064

***********************************************************

Reviewer Comments (if any, and for reference):