Browsing by Subject "Pyelonephritis"

Now showing 1 - 4 of 4
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    Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic Escherichia coli challenge
    (National Academy of Science, 2022) Canas, Jorge J.; Liang, Dong; Saxena, Vijay; Hooks, Jenaya; Arregui, Samuel W.; Gao, Hongyu; Liu, Yunlong; Kish, Danielle; Linn, Sarah C.; Bdeir, Khalil; Cines, Douglas B.; Fairchild, Robert L.; Spencer, John D.; Schwaderer, Andrew L.; Hains, David S.; Pediatrics, School of Medicine
    Antimicrobial peptides (AMPs) are critical to the protection of the urinary tract of humans and other animals from pathogenic microbial invasion. AMPs rapidly destroy pathogens by disrupting microbial membranes and/or augmenting or inhibiting the host immune system through a variety of signaling pathways. We have previously demonstrated that alpha-defensins 1-3 (DEFA1A3) are AMPs expressed in the epithelial cells of the human kidney collecting duct in response to uropathogens. We also demonstrated that DNA copy number variations in the DEFA1A3 locus are associated with UTI and pyelonephritis risk. Because DEFA1A3 is not expressed in mice, we utilized human DEFA1A3 gene transgenic mice (DEFA4/4) to further elucidate the biological relevance of this locus in the murine urinary tract. We demonstrate that the kidney transcriptional and translational expression pattern is similar in humans and the human gene transgenic mouse upon uropathogenic Escherichia coli (UPEC) stimulus in vitro and in vivo. We also demonstrate transgenic human DEFA4/4 gene mice are protected from UTI and pyelonephritis under various UPEC challenges. This study serves as the foundation to start the exploration of manipulating the DEFA1A3 locus and alpha-defensins 1-3 expression as a potential therapeutic target for UTIs and other infectious diseases.
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    Innate Immune Roles of Alpha-Defensin 1-3 in Neutralizing Uropathogenic Escherichia Coli
    (2024-05) Canas Kouaifati, Jorge Jose; Hains, David S.; Kaplan, Mark H.; Nelson, David E.; Dent, Alexander L.; Eadon, Michael T.
    Urinary tract infections (UTIs) are characterized by microbial colonization of the bladder, ureters or/and kidneys. Host-pathogen interactions compound to drive UTI susceptibility. The host innate immune system is composed of physio-chemical barriers and broad-spectrum potent effector responses that prevent pathogenic host colonization and bystander damage. Uropathogenic Escherichia coli (UPEC) isolates account for the majority of reported UTI cases. Virulence factors that are expressed by CFT073/UPEC heighten pathogenesis by permitting preferential invasion towards kidneys (pyelonephritis). During the acute invasion of the urinary tract tissues, pathogen molecular patterns and host-damage signals represent triggers that lead to host-defense responses. The release of antimicrobial peptides (AMPs) prevents microbial attachment to the epithelium. α-Defensin 1-3 are host-defense AMPs that work by eliciting microbial membrane interactions and inducing immunomodulatory effects. In humans, the DEFA1A3 locus encodes for three α-Defensin peptides (1-3). Chromosome 8 can harbor copy number polymorphism of the DEFA1A3 locus that range from 3-16 copies per diploid genome. Low copy numbers of DEFA1A3 have been associated with increased UTI risk in children (< 5 copies). On the other hand, patients with > 8 per copies per diploid genome have improved antibiotic therapy outcomes. In this thesis, we establish a pipeline to characterize α-Defensin 1-3 mechanisms of action, dissect contributors of expression at the cellular level, and protective DEFA1A3 gene-dose-dependent effects in the pyelonephritis setting. Using a manipulable mouse model expressing transgenic human DEFA1A3 gene copies, we explored dynamics of inducible α-Defensin 1-3 expression in the UPEC-infected kidney. Additionally, in vitro combinations of α-Defensin 1-3 and other host-defense AMPs work in concert to drive diverse cooperative action effects against UPEC. Methods and findings from my research in this thesis improve the current biomedical approaches to study AMP functions. Collectively, my results expand the understanding of DEFA1A3 polymorphic locus as a stratification UTI biomarker and exploration for the pre-clinical evaluation of kidney α-Defensin 1-3 expression as a potential therapeutic target for UTIs and other infectious diseases.
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    Pediatric kidney transplant recipients with and without underlying structural kidney disease have a comparable risk of hospitalization associated with urinary tract infections
    (Frontiers Media, 2022-09-02) Spiwak, Elizabeth; Nailescu, Corina; Schwaderer, Andrew; Pediatrics, School of Medicine
    Introduction: Urinary tract infections (UTIs) are a common and potentially serious kidney transplant complication. Pediatric kidney transplants are potentially at increased risk for UTIs when structural kidney disease is the underlying end-stage kidney disease (ESKD) etiology. The objective of this manuscript is to determine if children with structural kidney disorders are more prone to UTIs post kidney transplant. Materials and methods: Hospitalizations for pediatric kidney transplant recipients were retrospectively reviewed over a 4-year period for UTIs in the diagnostic codes. The patient's age, sex, graft age, underlying diagnosis for cause of ESKD, symptoms at presentation, urinalysis results, and urine culture results were recorded. UTI rates, febrile UTI rates, and UTI rates in the 1st year post-transplant were compared between children with ESKD due to structural vs. non-structural kidney disease. Results: Overall, 62 of 145 pediatric patients with kidney transplants accounted for 182 hospitalizations for kidney transplant complications over the 4-year study period. UTIs were components of 34% of the hospitalizations. Overall, UTI rates, febrile UTI rates, and UTI rates for the 1st year post kidney transplant were comparable for children with vs. without structural ESKD etiologies. Conclusion: Urinary tract infections are frequent components of hospitalizations for pediatric kidney transplant recipients. Children with and without structural kidney disease as an ESKD etiology have similar UTI rates indicating that UTI susceptibility is primarily due to the transplant process and/or medication regimens. UTIs represent a potentially modifiable risk factor for pediatric kidney transplant complications.
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    Ribonuclease 7 polymorphism rs1263872 reduces antimicrobial activity and associates with pediatric urinary tract infections
    (The American Society for Clinical Investigation, 2021) Pierce, Keith R.; Eichler, Tad; Mosquera Vasquez, Claudia; Schwaderer, Andrew L.; Simoni, Aaron; Creacy, Steven; Hains, David S.; Spencer, John D.; Pediatrics, School of Medicine
    Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7’s antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7’s antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7’s antibacterial activity.