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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.

Published onNov 30, 2023
Review 1: "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

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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



The study first indicates that secretory leukocyte protease inhibitor (SLPI) levels in the bladder increase in response to infection, using both a murine infection model and a human in vitro tissue culture model. The authors use complementary approaches with RT-qPCR and immunostaining to quantify SLPI levels across time. They show increase in SLPI transcript by 7h post infection but this does not correlate with immunostaining. Intriguingly, in the human tissue culture and early in infection, the authors detect high levels of SLPI but not corresponding increase in transcript. They then go on to demonstrate that in mice lacking SLPI, bacterial burdens are not affected, but inflammation is prolonged. They provide additional in vitro data with recombinant SLPI indicating that the protein does not have bactericidal function against E. coli – at least under the conditions tested. Transcriptional analysis between slp+/+ and slp-/- reveals broad effects on the regulation of several pathways. The authors end by evaluating levels of SLPI in the urine of human patients and finding a correlation between bacteriuria and higher SLPI levels. 

The manuscript by Rosen et al. describes the role of the antimicrobial peptide SLPI during urinary tract infection (UTI). The manuscript is clearly written, contains appropriate background information, and appropriately introduces the importance of studying SLPI in the context of UTIs. The work presented is novel and fills a critical gap in the field, which is understanding how the immune response is balanced in the bladder during UTI. 

Overall, the study is reliable and well executed for the most part. The conclusion that SLPI is involved in the response to UTI is well supported. There are convincing data that SLPI levels change in response to infection, but the specific contribution of urothelial versus other host defense cells recruited in response to infection is not clear in the manuscript, based on the differential information observed in vitro (using human cells) and in vivo (using mouse models). The data raise some questions regarding the inconsistencies between transcript and protein levels observed. For example, is it known whether SLPI is be stored in granules like neutrophil elastase (NE) and released upon stimulation? Here a RT-qPCR positive control of something known to have increased expression in the models used would greatly strengthen the observations. The data using the slp-/- mice is also strong, indicating a higher inflammation score. The least well-analyzed data – and one of the two reasons we rated the manuscript a “reliable” as opposed to “strong” rating – are the RNAseq experiments. The mock WT to mock slp-/- comparisons should be discussed more deeply, as they demonstrate the SLPI-specific changes in baseline expression of host genes. Additionally, the presented output data in the infected animals are described in a very broad manner and are overall inconclusive other than to suggest that SLPI contributes to the host response to UTI. Again, there are some key questions that remain: For example, elegant chronic infection models exist in the UTI field. What are the SLPI levels in mice that are chronically infected for over four weeks? Is there a correlation of lower SLPI levels, higher NE in chronically infected mice? The lack of these experiments is the second reason we rated this study as “reliable” as opposed to “strong”. The authors later on indicate higher SLPI levels in urine samples from women with acute bacteriuria, which further connects SLPI and UTI response, but the data samples could be strengthened by measurement of neutrophil elastase and its association with SLPI levels. Some food-for-thought points that did not affect the overall rating: Are there other patient populations with published urine proteomics data that could be mined for SLPI levels? Particularly thinking of patient populations with suspected epithelial damage/dysplasia—bladder cancer, interstitial cystitis, etc. Is elevated SLPI a general inflammatory response or specific to UTI? 

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