Secretory leukocyte protease inhibitor protects against severe urinary tract infection in mice

  1. Anne L. Rosen
  2. Michael A. Lint
  3. Dayne H. Voelker
  4. Nicole M. Gilbert
  5. Christopher P. Tomera
  6. Jesús Santiago-Borges
  7. Meghan A. Wallace
  8. Thomas J. Hannan
  9. Carey-Ann D. Burnham
  10. Scott J. Hultgren
  11. Andrew L. Kau

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Abstract

Annually, millions of people suffer from urinary tract infections (UTIs) and more than $3 billion are spent on work absences and treatment of these patients. While the early response to UTI is known to be important in combating urinary pathogens, knowledge of host factors that help curb infection is still limited. Here, we use a preclinical model of UTI to study secretory leukocyte protease inhibitor (SLPI), an antimicrobial protein, to determine how it protects the bladder against infection. We find that SLPI is increased during UTI, accelerates the clearance of bacteriuria, and upregulates genes and pathways needed to fight an infection while preventing prolonged bladder inflammation. In a small clinical study, we show SLPI is readily detectable in human urine and is associated with the presence of a uropathogen in patients without a previous history of UTI, suggesting SLPI may play an important role in protecting from bacterial cystitis.

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  1. Version published to 10.1128/mbio.02554-23
  2. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10253774.

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction explains the objective of the research well. It mentions the background of why they are studying UPEC caused by UTI, how they are performing their tests, and their findings. It is clearly written and detailed.
    Are the methods well-suited for this research? Somewhat appropriate There were many methods performed for this study, including using a mouse model, and analyzing data from a human study. For the mouse model, SLPI +/+ and SLPI -/- were studied. These are appropriate for the study as this study is analyzing the effect of SLPI, but heterozygous SLPI +/- were not studied. This would have been beneficial to see how a heterozygous SPLI mouse would react to a UTI. These mice were only female, so including male mice is beneficial to see if there is a different reaction between female and male mice infected with a UTI. Since the behavior of SLPI in the human urinary tract during UTI is not well known, this study analyzed the behavior through clinical data provided by a hospital. This clinical data only includes women 18-49. It would be beneficial to also analyze male SLPI behavior as males are also susceptible to UTIs. The age range could also be improved as children are susceptible to UTIs. There were only 16 samples for the human part of the study, which is not an ideal sample size for a study. There should be more samples in order to draw appropriate conclusions, as each sample holds a strong weight in the conclusions currently. Although this study mentions only a few times that their findings are based on women, if all of their methods include female samples, this should be disclosed in the title, which it is not. The methods section of the paper is very clear with headers and what each assay and test includes.
    Are the conclusions supported by the data? Somewhat supported The paper's main conclusion is that mice lacking SLPI are more susceptible to severe UTI, and have increased urine NE at baseline. They also conclude that SLPI is an important factor that repels bacterial pathogens within the urinary tract. In this discussion section where they describe their conclusions based on their data, they do not mention these conclusions are female-specific, which is highly important to disclose. Their conclusions can be more accurate and descriptive if they mention it is only for female SLPI mice. Besides this, the conclusions are well supported by the data, and it is well organized where the authors describe a conclusion and specifically which data they are using to support their conclusion.
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear The data presentations and visualizations are very clear. There is one figure for each conclusion drawn and many sub figures to describe the data clearly. The description for each figure is done appropriately too, including the test performed, such as t-test, ANOVA, and the laboratory procedure, such as rt-qPCR. The color codes on each figure enhance the understanding of the figure as well. Overall, the figures do a great job of helping the reader to understand the results and conclusions, and the figures are presented in a clear manner to easily see patterns. The drawings are also done appropriately, including in Figure 4 that shows a schematic of the experimental approach, and is a good supplement to reading the experimental approach if it is not understood well.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly The authors discuss the potential for future findings several times in the discussion, after describing each conclusion, interpreting the results, and what they suggest to do in the future. In the discussion section of the paper, the authors clearly highlight the results they found and how they interpret the results. Some of them are supplemented with previous publications and findings to strengthen their argument. The authors also clearly describe the limitations of their study, and how future studies they suggest can help with the limitations of this study. One example is that they describe their findings where bladder cells contain a reservoir of SLPI that is released following pathogen challenge, and a limitation is that they do not know if SLPI originates from recruited neutrophils, so they suggest a future experiment with tissue-specific deletion of SLPI to truly determine the cellular origins of SLPI in the urinary tract during infection. The authors ensure that their result interpretations and next steps are in a order/pattern that makes it easy to read and follow along.
    Is the preprint likely to advance academic knowledge? Somewhat likely The preprint describes how they are specifically studying SLPI as it is not well characterized in UTIs. Since this preprint presents knowledge of a large player in UTI infections that other papers have not, this preprint is likely to advance academic knowledge, and has the potential to be a starting point for new UTI treatments in women. Especially, since this preprints main overall conclusion includes that SLPI protects against UTI in mice and provides evidence that SLPI is regulated in response to uropathogenic exposure in women. The paper suggests multiple future pathways to take based on this paper, which could strengthen this paper's conclusions more, and help with advancing academic knowledge. I did not say this preprint is highly likely to advance academic knowledge due to some limitations this paper acknowledges, such as limited knowledge in the effect of passenger mutations, and since this paper focuses on women, and does not include men, even though UTIs affect both sexes.
    Would it benefit from language editing? Yes There are limited grammatical errors, but some phrases require some language editing to provide more detailed descriptions of the conclusions and methods. One example is it was not mentioned much that this paper only studies females in the conclusions.
    Would you recommend this preprint to others? Yes, but it needs to be improved I would recommend this preprint to others as it provides immense knowledge of the role SLPI plays in urinary tract infections that other papers do not. It provides detail of SLPI and urinary tract infections that could be beneficial for others studying UTIs. There are a few improvements that could be made, such as more detailed writing, clearer descriptions, and future papers that consider the limitations of this paper and continue onto this paper's future research desires. This paper serves as a good starting point in learning about SLPI in UTIs but should not be fully trusted until improvements and future studies can support the conclusions of this paper.
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes Some minor changes include tweaking the language of the writing in some areas of the paper, which an editor would point out. A publisher would most likely ask for some clarification in some portions of this paper, so after minor changes, this paper would be ready for attention.

    Competing interests

    The author declares that they have no competing interests.

  3. Rapid Reviews Infectious Diseases

    Niels Frimodt-Moller

    Review 2: "Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice"

    Reviewers suggested additional experiments in chronic UTI and other urothelial damage conditions to further support the role of SLPI in balancing inflammation.

  4. Rapid Reviews Infectious Diseases

    Maria Hadjifrangiskou, Seth Reasoner

    Review 1: "Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice"

    Reviewers suggested additional experiments in chronic UTI and other urothelial damage conditions to further support the role of SLPI in balancing inflammation.

  6. Version published to 10.1101/2023.10.10.561753v1 on bioRxiv