Cellular and Molecular Basis of Sex Specificity in UTI Pathogenesis

UTI 发病机制中性别特异性的细胞和分子基础

基本信息

批准号：
10094726
负责人：
Ashlee Miriam Earl
金额：
$ 48.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094726
关键词：
Acute Affect Anatomy Androgen Receptor Androgenization Androgens Antibiotics Automobile Driving Bacteria Bacterial Infections Bacterial RNA Biological Assay Bladder Bypass Catheters Cell Culture System Cell Nucleus Child Chronic Cystitis Chronic Kidney Failure Cicatrix Collaborations Communities Complement Factor B Complex Complication Data Epidemiology Epithelial Cells Escherichia coli Infections Exhibits Female Flow Cytometry Functional disorder Gastrointestinal tract structure Gene Expression Genetic Transcription Gonadal Steroid Hormones Health Healthcare Histology Hormonal Human Hybrids Hypertension Immune response In Vitro Inbred C3H Mice Incidence Infection Infective cystitis Kidney Knock-out Knockout Mice Laboratories Leukocytes Life Link Mediator of activation protein Methods Microscopy Modeling Molecular Morbidity - disease rate Mouse Strains Mus Myofibroblast Operative Surgical Procedures Outcome Pathogenesis Pathogenicity Pathway interactions Phenotype Polycystic Ovary Syndrome Population Pre-Clinical Model Predisposition Publishing Pyelonephritis Recurrence Resolution Risk SHH gene Severities Sex Differences Signal Pathway Signal Transduction Site Specific qualifier value Specificity Techniques Technology Testing Time To specify Transforming Growth Factors Tubular formation Universities Urethra Urinary tract Urinary tract infection Uropathogenic E. coli Vesico-Ureteral Reflux Virulence Virulence Factors Washington Woman Work activin A cell type conditional knockout epidemiologic data experimental study in vivo infection management infection risk innovation insight kidney fibrosis kidney infection macrophage male men minimally invasive mortality mutant novel pathogen patient population pre-clinical prevent programs recruit renal abscess renal epithelium renal scarring response sex transcriptome sequencing young adult

项目摘要

PROJECT SUMMARY In the proposed work, the Hunstad laboratory at Washington University will employ new models of urinary tract infection (UTI) in female, androgenized female, and male mice to determine molecular mechanisms by which host androgen exposure promotes uropathogenic Escherichia coli (UPEC) pyelonephritis as well as renal scarring, a common sequela of upper-tract UTI. Our recent findings indicate that the influence of sex, including androgen exposure, on these common bacterial infections is more complex than previously appreciated. Using newly developed and optimized models of UTI in mice, we recently demonstrated that androgen exposure is associated with increased risk for chronic cystitis and high-titer pyelonephritis, as well as formation of renal abscesses, in both male and female hosts. These findings correlate with epidemiologic data revealing higher morbidity and mortality in men who do suffer complicated UTI (compared with women), and higher incidence of UTI in women with a common hyperandrogenic condition (polycystic ovary syndrome). Moreover, we have demonstrated a separable effect of androgens on renal fibrosis (scarring), a common complication of pyelonephritis in children that can contribute to long-term sequelae such as hypertension and risk for chronic kidney disease. On the basis of these findings, we hypothesize that fundamental sex differences impact the host-pathogen interaction and cellular responses in pyelonephritis, thereby influencing pathogenicity, resolution, and subsequent renal scarring. To interrogate this hypothesis, and building on our published work, we will first comprehensively define host-sex-specific virulence requirements and sex influences on the host- pathogen interaction through single-nucleus RNA-seq, hybrid capture-enhanced bacterial RNA-seq, and insertion-site sequencing experiments on the infected kidney, in collaboration with MPI Dr. Earl and collaborator Dr. Humphreys. Candidate sex-discrepant host pathways and bacterial virulence factors will be confirmed and interrogated using germline and conditional knockout mice, bacterial mutants, and an array of bacterial pathogenesis studies. We will also define the molecular pathways underlying renal fibrosis following pyelonephritis, and how these pathways are modulated by sex and/or by androgen exposure at varying times before, during, and after UTI. In total, the proposed work will leverage new preclinical models and an array of conventional and cutting-edge experimental techniques. Our results will illuminate sex-specific host-pathogen interactions in the infected kidney and identify UPEC virulence factors important in sex-dependent outcomes of upper-tract UTI. In addition, our preclinical findings will also be translationally relevant to recurrent UTI and renal scarring in human patient populations.

项目概要在拟议的工作中，华盛顿大学的 Hunstad 实验室将采用新的泌尿道模型雌性、雄激素化雌性和雄性小鼠感染（UTI），以确定其分子机制宿主雄激素暴露会促进尿路致病性大肠杆菌 (UPEC) 肾盂肾炎以及肾病疤痕是上尿路感染的常见后遗症。我们最近的研究结果表明，性别的影响，包括雄激素暴露对这些常见细菌感染的影响比以前认识的更为复杂。使用新开发和优化的小鼠尿路感染模型，我们最近证明雄激素暴露与慢性膀胱炎和高滴度肾盂肾炎以及形成的风险增加有关男性和女性宿主的肾脓肿。这些发现与流行病学数据相关患有复杂性尿路感染的男性（与女性相比）发病率和死亡率更高，并且患有常见高雄激素性疾病（多囊卵巢综合征）的女性尿路感染的发病率。而且，我们已经证明雄激素对肾纤维化（疤痕）具有可分离的作用，肾纤维化是肾纤维化的常见并发症儿童肾盂肾炎可能导致长期后遗症，例如高血压和慢性肾病风险肾脏疾病。根据这些发现，我们假设基本的性别差异会影响肾盂肾炎中宿主-病原体相互作用和细胞反应，从而影响致病性，解决，以及随后的肾脏疤痕。为了质疑这一假设，并以我们已发表的工作为基础，我们将首先全面定义宿主性别特异性毒力要求以及性别对宿主的影响通过单核 RNA-seq、混合捕获增强的细菌 RNA-seq 和病原体相互作用与 MPI Earl 博士合作，对受感染的肾脏进行插入位点测序实验合作者汉弗莱斯博士。候选性别差异宿主途径和细菌毒力因子将是使用种系和条件敲除小鼠、细菌突变体和一系列细菌发病机制研究。我们还将定义肾纤维化的分子途径如下肾盂肾炎，以及这些途径如何通过性别和/或不同时间的雄激素暴露来调节尿路感染之前、期间和之后。总的来说，拟议的工作将利用新的临床前模型和一系列传统和前沿的实验技术。我们的结果将阐明性别特异性宿主病原体受感染肾脏中的相互作用，并确定对性别依赖性结果很重要的 UPEC 毒力因子上尿路感染。此外，我们的临床前研究结果也将与复发性尿路感染和人类患者群体中的肾脏疤痕。