Establishing a model of recurrent/chronic urinary tract infection in lupus-prone mice

建立狼疮易感小鼠复发/慢性尿路感染模型

• 批准号: 10573019
• 负责人: STEFANIA GALLUCCI
• 金额: $ 8.38万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-18 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573019
• 关键词: Abscess; Acceleration; Affect; Amyloid; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial DNA; Bacterial Infections; Bacteriuria; Bladder; Cells; Chromatin; Chronic; Clinical; Collaborations; Complex; DNA; Development; Disease; Endotoxins; Escherichia coli; Experimental Models; Exposure to; Female; Flare; Genetic Predisposition to Disease; Goals; Gram-Negative Bacteria; Human; Immune; Immune response; Immune system; Individual; Infection; Inflammatory; Innate Immune Response; Interferon Type I; Link; Literature; Lupus; Mediating; Microbial Biofilms; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Pathogenesis; Patients; Pneumonia; Population; Predisposition; Production; Protocols documentation; Publishing; Recurrence; Reporting; Role; Sepsis; Serum; Severities; Stimulus; Systemic Lupus Erythematosus; TLR2 gene; Testing; Therapeutic immunosuppression; Urinary Microbiome; Urinary tract infection; Uropathogenic E. coli; Woman; adaptive immune response; anti-dsDNA antibodies; autoimmune pathogenesis; cell community; cohort; cytokine; ds-DNA; epidemiology study; genetic makeup; immune self tolerance; infection rate; inflammatory marker; intraperitoneal; lupus prone mice; microbial products; microbiome; mortality; mouse model; mutant; novel therapeutic intervention; pathogen; soft tissue; tool; translational study

PROJECT SUMMARY Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a complex pathogenesis, in which environmental triggers act in individuals with a genetic susceptibility to break immunological self-tolerance. Urinary tract infections (UTI) are among the most common infections in patients with SLE. We have recently reported that a subset of female patients with SLE, who have asymptomatic persistent bacteriuria, show higher levels of pro-inflammatory markers and disease flares. These patients have high levels of anti-dsDNA antibodies (Abs) that correlate with high levels of Abs against curli/DNA, a bacterial amyloid complexed with bacterial DNA. Curli/DNA is produced by Gram-negative bacteria, like UroPathogenic Escherichia coli (UPEC), a frequent cause of bacteriuria and UTI. Translational and epidemiological studies indicate that patients with SLE are frequently exposed to microbial products and suggest that bacterial infections may promote SLE in predisposed individuals, but the underlying mechanisms remain unknown. We have also reported that curli/DNA can accelerate lupus onset in lupus-prone mice and activate immune cells to secrete type I Interferons (IFNs), a cytokine important in lupus pathogenesis. We hypothesize that recurrent mucosal infections, like UTI, which remain often untreated because subclinical in women, may provide a repetitive immune stimulus in individuals genetically susceptible to autoimmunity and trigger lupus onset or flares. The objective of this R03 application is to establish a mouse model of UTI in lupus-prone mice that can be used to study how recurrent or chronic bacteriuria contribute to lupus disease. In Aim 1. we will establish a model of recurrent/chronic UTls in lupus prone mice by using a lab strain of UPEC, which express curli amyloid, and adapting the conditions of inoculation previously established in WT mice. We will study the ability of bacteria to establish biofilms in the bladder, whether they become systemic and activate the immune system in lupus prone mice vs WT mice. We will analyze the induction of autoantibodies as markers of onset of autoimmunity. Comparing a strain of UPEC that expresses curli amyloid and its curli-deficient mutant, we can determine the role of curli in UTI. In Aim 2. we will test three clinical UPEC isolates from patients with SLE and persistent bacteriuria to establish an infection relevant for patients living with SLE. The successful completion of this project will provide a protocol that lupus experts can use to study the mechanisms for the role of bacterial mucosal infections, like the subclinical UTls occurring in patients living with SLE, in the pathogenesis of autoimmune diseases. It may highlight curli amyloid as pivotal stimulus in infection-induced autoimmunity. Finally, it will generate a tool to test novel therapeutic approaches in lupus through the control of subacute infections and the re-establishment of the correct urinary microbiome.

项目摘要 系统性红斑狼疮（SLE）是一种发病机制复杂的自身免疫性疾病， 环境触发因素在具有遗传易感性的个体中起作用，以打破免疫学自身耐受性。 尿路感染（UTI）是SLE患者最常见的感染之一。我们最近 报道，女性SLE患者的一个子集，谁有无症状的持续菌尿，显示较高的 促炎标志物和疾病爆发的水平。这些患者体内有高水平的抗dsDNA抗体 (Abs)这与高水平的抗卷曲/DNA抗体相关，卷曲/DNA是一种与细菌DNA复合的细菌淀粉样蛋白。 Curli/DNA是由革兰氏阴性菌产生的，如尿路致病性大肠杆菌（UPEC）， 细菌尿和尿路感染转化和流行病学研究表明，SLE患者经常 暴露于微生物产品，并表明细菌感染可能促进易感个体的SLE， 但其潜在机制仍不清楚。我们还报道了curli/DNA可以加速狼疮 在狼疮易感小鼠中发病，并激活免疫细胞分泌I型干扰素（IFN）， 狼疮发病机制我们假设，复发性粘膜感染，如尿路感染，这仍然经常未经治疗， 因为在女性中是亚临床的，可能会在遗传易感的个体中提供重复的免疫刺激， 自身免疫并引发狼疮发作或复发。本R 03申请的目的是建立一个 狼疮易感小鼠的UTI小鼠模型可用于研究复发性或慢性菌尿如何发生 会导致狼疮在目标1中。我们将在狼疮易感小鼠中建立复发/慢性UTLs模型， 利用表达curli淀粉样蛋白的UPEC实验室菌株， 在WT小鼠中建立。我们将研究细菌在膀胱中建立生物膜的能力， 变得全身性并激活狼疮易感小鼠与WT小鼠的免疫系统。我们将分析归纳 自身抗体作为自身免疫发病的标志。表达卷曲淀粉样蛋白的UPEC菌株的比较 及其curli缺陷突变体，我们可以确定curli在UTI中的作用。在目标2中。我们将测试三个临床UPEC 分离自SLE和持续性菌尿患者，以建立与SLE患者相关的感染， SLE。 该项目的成功完成将提供一个协议，狼疮专家可以用来研究 细菌粘膜感染的作用机制，如生活在 SLE，在自身免疫性疾病的发病机制中。它可能突出卷曲淀粉样蛋白作为感染诱导的关键刺激， 自身免疫最后，它将产生一种工具，通过 控制亚急性感染和重建正确的尿液微生物组。