Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Pseudomonas aeruginosa Infection by Suppression of Inflammation Rather Than Microbial Killing

Osbourn, Megan; Rodgers, Aoife M.; Dubois, Alice; Small, D.; Humphries, Fiachra; Delagic, Nezira; Moynagh, Paul N.; Weldon, Sinéad; Taggart, Clifford C.; Ingram, Rebecca J.

doi:10.3390/biom12121728

“…While we cannot exclude the possibility that SLPI inhibits UPEC growth under different in vitro conditions or only in vivo , cathelicidin (LL-37), another antimicrobial peptide found in the urinary tract ( 29 ), demonstrated high potency in the same assay. Our results are consistent with previous findings of P. aeruginosa infection of the airway ( 87 ) and suggest that the immunomodulatory functions of SLPI mediate its protective effects in our model of UTI.…”

Section: Discussionsupporting

confidence: 93%

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

Rosen,

Lint,

Voelker

et al. 2024

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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 preclinical 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 a history of recent or recurrent UTI, suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI promotes clearance of UPEC in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women. IMPORTANCE 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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“…While we cannot exclude the possibility that SLPI inhibits UPEC growth under different in vitro conditions or only in vivo , cathelicidin (LL-37), another antimicrobial peptide found in the urinary tract (29), demonstrated high potency in the same assay. Our results are consistent with previous findings of P. aeruginosa infection of the airway (78) and suggest that the immunomodulatory functions of SLPI mediate its protective effects in our model of UTI.…”

Section: Discussionsupporting

confidence: 93%

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice

Rosen,

Lint,

Voelker

et al. 2023

Preprint

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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.

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“…Mice were infected intranasally with a clinical mucoid isolate of P. aeruginosa Q502 which originated from the sputum of a patient with CF (provided by the Clinical Microbiology Laboratory in the Royal Victoria Hospital, Belfast) (21) or PAO1 which was kindly provided by Prof Scott Bell (University of Queensland, Australia). Infections were performed as previously described (22). In brief, P. aeruginosa was grown to mid-log phase in nutrient broth and washed extensively using endotoxin-free sterile phosphate buffered saline (PBS).…”

Section: Infection Of Mice With P Aeruginosamentioning

confidence: 99%

Regulatory T cells mediate the decreased susceptibility of males to Pseudomonas aeruginosa infection

Rodgers,

Monahan,

Dubois

et al. 2023

Preprint

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Background Sex hormones have been shown to play a role in the susceptibility of female patients with CF to P. aeruginosa chronic infection; however, the cellular mechanisms responsible for such sex-based imbalance are poorly understood. Accordingly, the aim of this study was to assess the role of the female sex hormone estrogen in a murine model of P. aeruginosa induced lung infection and to elucidate the cellular immune mechanisms involved. Methods The bacterial burden and inflammatory parameters following intranasal infections with P. aeruginosa were compared in male and female mice. Female mice were treated with anastrozole, which lowers estradiol, and the impact on survival assessed. Infection in male and female RAG1−/− mice, which lack T and B lymphocytes, and Foxp3DTR/GFP mice, in which Tregs can be selectively depleted, were also compared. Results We demonstrate that female adult mice are more susceptible to P. aeruginosa lung infection, compared to that of males, while this effect was not evident in pre-pubescent mice. Pre-treatment of female adult mice with anastrozole, resulted in increased survival and a greater ability to control P. aeruginosa induced lung infection, as evidenced by reduced bacterial burden in the lung and reduced levels of serum IL-6. This increased susceptibility of adult female mice to P. aeruginosa was not seen during infection in RAG1−/− mice, or following depletion of regulatory T cells (Tregs) in Foxp3DTR/GFP mice. In male mice, there was a significant increase in IL-6 levels following Treg depletion, demonstrating liberation from regulation, which did not occur in female mice. Conclusions This data demonstrates, for the first time, that the increased susceptibility of female mice to P. aeruginosa-induced lung infection is a result of the reduced action of Tregs. The potential benefits of targeting Treg activity in CF warrants further investigation in prevention and treatment of P. aeruginosa infection.

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Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Pseudomonas aeruginosa Infection by Suppression of Inflammation Rather Than Microbial Killing

Cited by 7 publications

References 50 publications

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

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

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice

Regulatory T cells mediate the decreased susceptibility of males to Pseudomonas aeruginosa infection

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