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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.

Published onNov 30, 2023
Review 2: "Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice"
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Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice
Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice
Description

Abstract Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a mouse model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC infected SLPI-deficient (Slpi-/-) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi-/- mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18-49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with history of recent or recurrent UTI (rUTI), suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI protects against acute UTI in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

There is a lack in our understanding of the natural immune defense against urinary tract infection. In this study, a peptide called Secretory Leukocyte Protease Inhibitor is shown to increase in the urine during E. coli infection in normal mice, and in mice without the ability to produce the peptide, the same type of infection has a worse course. Therefore, this peptide seems to protect the bladder against infection. 

The study by Rosen et al. finds that SLPI is involved in UTI in both mice and humans, and that it may have implications in recurrent UTI. The study gets around the importance of SLPI in an elegant way including knock-out mice, monitoring mRNA of protein synthesis in the bladder etc. I find the data convincing as proof of a role of SLPI. There are however some issues in the presentation of the results that can be discussed and need improvement. These are as follows:

  1. The title reports to “severe” UTI in mice; what classifies the model and strain used as severe? 

  2. Usually, when measuring protein concentrations in urine such as peptides, and since the urine volume sampled can vary, there is a need to measure an “internal standard” such as creatinine and report the results as a protein/creatinine ratio. Here, protein concentrations are reported directly as weight or micromole/ml. Could the non-increase in SLPI in women with a history of rUTI be related to this fact? Is there an explanation for not relating to creatine or other urinary markers?

  3. What was the reason for introducing kanamycin-resistance in the E. coli isolate used – and did it interfere with gentamicin-susceptibility?

    Figures:

    • Hpi and dpi should be explained in figure legends, even if they are explained in the text.

    • Boxplots should be explained (median, mean etc.) in all figures. The same for histograms: Means or medians, SDs etc.

    • In Figure 3 it seems that bars are equidistant around the points, which are means? SDs on a log-scale usually are longer below the mean than above. And usually log CFUs are presented as medians and range/quartiles, and non-parametric tests used, in stead as T-test as explained here?

    • The bladder histology in Figure 5 is hard to see with such small figures – they could enlarge the relevant portions of the histology pictures where this is needed to explain the differences, as proposed. Again, explain histograms in Figure 5B, means or medians etc.? In Figure 5D, again looks like means with SD bars of same length?

  4. References:
    The authors need to revise the references. E.g. numbers 30, 32, 45, 47 and 50 miss the names of the Journal, where the papers are published. Some Journals are abbreviated, others not – follow the rules of this journal. Ref. no. 32 is completely wrong: “Kommunehospital” is not a person name, it is the name of a hospital in Copenhagen, and what is “Gyne”? Do you need to mention when a Journal was accessed on the net? Why not just mention the reference? (e.g., ref. no 34). 

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