Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic
            <i>Escherichia coli</i>
            challenge

Canas, Jorge; Liang, Dong; Saxena, Vijay; Hooks, Jenaya; Arregui, Samuel; Gao, Hongyu; Liu, Yunlong; Kish, Danielle D.; Bdeir, Khalil; Cines, Douglas B.; Fairchild, Robert L.; Spencer, John David; Schwaderer, Andrew L.

doi:10.1073/pnas.2206515119

Cited by 10 publications

(16 citation statements)

References 42 publications

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“…79 More recently, mice expressing human DEFA1A3 defensin on UTI showed that DEFA1A3 is expressed by CD cells and is upregulated on UTI, and the mice display a better protection against kidney and bladder infection compared with control animals. 80 Finally, this study demonstrated a synergistic effect of HNP1-3 with cathelicidin against UPEC and antibiotic-resistant strains of E. coli . Similarly, human b-defensin 1 is upregulated three times in pyelonephritis, 81 and mice lacking this protein have higher UPEC titers in their urine.…”

Section: Mechanistic Insights Into Intercalated Cells and Their Role ...mentioning

confidence: 61%

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Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

Chelangarimiyandoab,

Mungara,

Batta

et al. 2023

JASN

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Urinary tract infections (UTIs) affect more than 1 in 2 women during their lifetime. Among these, more than 10 % of patients carry antibiotic-resistant bacterial strains, highlighting the urgent need to identify alternative treatments. While innate defence mechanisms are well characterized in the lower urinary tract, it is becoming evident that the collecting duct, the first renal segment encountered by invading uropathogenic bacteria, also contributes to bacterial clearance. However, the role of this segment is beginning to be understood. This review summarizes the current knowledge on collecting duct intercalated cells in urinary tract bacterial clearance. Understanding the innate protective role of the uroepithelium and of the collecting duct offers new opportunities for alternative therapeutic strategies.

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Section: Mechanistic Insights Into Intercalated Cells and Their Role ...mentioning

confidence: 61%

“…85 Finally, cathelicidin was found to have a synergistic effect with HNP1-3 while it has an additive effect with RNase 7. 80 More synergistic effects may exist but have not been characterized yet.…”

Section: Amp Synergistically Contribute To the Host Defensementioning

confidence: 99%

Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

Chelangarimiyandoab,

Mungara,

Batta

et al. 2023

JASN

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“…While they can be constitutively expressed, production of AMPs is also induced by microbial stimuli and tissue damage ( 27 , 28 ). While AMPs including cathelicidin ( 29 – 31 ), defensins ( 32 – 35 ), ribonucleases ( 36 – 39 ), and serpins ( 24 ), have been studied in the context of UTI, little is known about the roles and functions of the well-characterized AMP secretory leukocyte protease inhibitor (SLPI) which is also found in the urogenital tract ( 40 , 41 ). SLPI has been extensively studied in the respiratory tract ( 42 ), but has also been shown to help combat urogenital infections from HIV, gonorrhea, and Candida yeast ( 43 – 45 ), though its function in bacterial UTIs remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Rosen,

Lint,

Voelker

et al. 2024

mBio

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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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“…α-Defensin 1-3 are AMPs that participate in the innate immune response to exert both neutralizing and immunomodulatory roles against microbes. Previous studies have characterized α-Defensin 1-3 as a novel biomarker in pediatric and adult UTIs that can be expressed by neutrophils and collecting duct epithelia in the infected kidney (9,10,11,12,13,14,15). Encompassing 5-12% of the human genome, DNA copy-number variations (CNVs) are repeated genomic regions that can affect the expression of a gene in a dosage-dependent manner, and the DEFA1A3 locus ranges between 2 and 18 diploid copies in individuals (16,17).…”

Section: Introductionmentioning

confidence: 99%

“…Because mice lack a homolog, investigating the role of DEFA1A3 DNA CNVs in the mechanism(s) of host defense against uropathogens has not been extensively explored. To circumvent these limitations, a transgenic mouse with a knock-in of the human DEFA1A3 gene has been used to study α-Defensin 1-3/DEFA1A3 roles using in vivo models of UTIs (9,20,21).…”

Section: Introductionmentioning

confidence: 99%

DEFA1A3DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection

Canas,

Arregui,

Zhang

et al. 2024

Life Sci. Alliance

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Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations inDEFA1A3have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically, children with lower DNA copy numbers were more susceptible to UTIs. The mechanism of action by which α-Defensin 1-3/DEFA1A3copy-number variations lead to UTI susceptibility remains to be explored. In this study, we use a previously characterized transgenic knock-in of the humanDEFA1A3gene mouse to dissect α-Defensin 1-3 gene dose–dependent antimicrobial and immunomodulatory roles during uropathogenicEscherichia coli(UPEC) UTI. We elucidate the relationship between kidney neutrophil– and collecting duct intercalated cell–derived α-Defensin 1-3/DEFA1A3expression and UTI. We further describe cooperative effects between α-Defensin 1-3 and other AMPs that potentiate the neutralizing activity against UPEC. Cumulatively, we demonstrate thatDEFA1A3directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage–dependent manner.

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Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic Escherichia coli challenge

Cited by 10 publications

References 42 publications

Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens

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

DEFA1A3DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection

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