Harnessing Antibody Responses to Prevent and Treat Urinary Tract Infections

利用抗体反应预防和治疗尿路感染

• 批准号: 10344461
• 负责人: Andrew Leon Kau
• 金额: $ 63.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-10 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344461
• 关键词: Activities of Daily Living; Address; Adherence; Affect; Affinity; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Formation; Antibody Response; Antibody Specificity; Area; B-Lymphocytes; Bacterial Adhesins; Binding; Bladder; Blocking Antibodies; Cells; Coal; Communicable Diseases; Communities; Cystitis; Data; Development; Diagnostic; Distal; Epithelial; Epitopes; Equilibrium; Escherichia coli; Extended-spectrum β-lactamase; Gastrointestinal tract structure; Generations; Genome; Gnotobiotic; Host Defense Mechanism; Human; Immune; Immune System Diseases; Immunization; Immunoglobulin G; Immunoglobulin-Secreting Cells; Impairment; Infection prevention; Invaded; Light; Mannose; Mannosides; Mediating; Modeling; Molecular Conformation; Monkeys; Monoclonal Antibodies; Mucous Membrane; Multi-Drug Resistance; Mus; Mutation; Operon; Oral; Oral Administration; Passive Immunization; Pathogenesis; Pathogenicity; Patients; Persons; Phase Ia/Ib Clinical Trial; Pilum; Prevalence; Prevention; Production; Public Health; Recombinants; Recurrence; Research; Resistance; Resolution; Role; Seeds; Serinus; Signal Transduction; Specificity; Surface; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Uses; Thinking; Time; United States; Urinary tract; Urinary tract infection; Urine; Uropathogen; Uropathogenic E. coli; Vaccinated; Vaccination; Vaccines; Virus Diseases; Woman; ascending urinary tract infection; bacterial community; base; cancer therapy; combat; design; effectiveness testing; fluoroquinolone resistance; gut colonization; gut microbiota; human monoclonal antibodies; humanized monoclonal antibodies; in vivo; microbial community; mouse model; mucosal vaccination; prevent; receptor; resistant strain; response

SUMMARY Urinary tract infections (UTIs) affect 15 million women in the United States every year and treatment for UTIs is becoming more difficult due to high rates of antibiotic resistance. Further, UTIs are highly recurrent. Between 20 and 40% of UTI episodes are followed by recurrent UTIs (rUTIs), with some women suffering as many as 6 or more recurrences per year. Uropathogenic Escherichia coli (UPEC) is the major causative agent of UTIs. Antibiotic resistance within UPEC isolates is rising, and the emergence of extended-spectrum beta-lactamase producing and fluoroquinolone resistant strains is a serious public health concern. Type 1 pili, tipped with the mannose binding FimH adhesin have been shown to be essential for bladder colonization and UTI pathogenesis in multiple mouse models. FimH mediates binding to mannosylated uroplakins lining the bladder surface to facilitate colonization and invasion into bladder cells where they rapidly replicate into intracellular bacterial communities that protect UPEC from immune cells and antibiotics. In addition, FimH facilitates the ability of UPEC to establish a reservoir in the GIT, from where they can seed UTIs by ascending from the periurethral area into the bladder. While UPEC are genetically variable, FimH is part of the core E. coli genome, although rare strains have been found with mutations in the type 1 operon. Immunization against FimH protects against UPEC UTI in murine and monkey cystitis models and a FimH-based vaccine has been allowed by the FDA for patients suffering from multi-drug resistant UPEC. In animal models, protection is antibody-mediated, as FimH- specific IgG antibodies are found in the urine from protected animals and can protect from UTI through passive transfer. Intriguingly, UPEC abundance in the gut is increased at the time of symptomatic UTI, suggesting that gut colonization is a key step in the rUTI cycle. Additionally, studies in this proposal show that eliciting a mucosal antibody response against FimH can reduce UPEC colonization of the gut. In light of these findings, this proposal addresses the hypothesis that anti-FimH induced antibodies can combat rUTI by two distinct mechanisms: i) prevention of UPEC binding to the uroepithelium; and ii) interference with UPEC colonization of the GIT, thereby lowering the likelihood of UPEC introduction into the urinary tract. The aims of this proposal are to: i) determine how mucosal vaccination against FimCH reduces UPEC gut colonization (Aim 1); ii) exploit vaccine induced B cell responses to isolate monoclonal antibodies (mAbs) to FimH and determine their epitope specificity (Aim 2); and iii) use these mAbs in mouse models of GIT colonization and cystitis in order to elucidate mechanisms of protection (Aim 3). The research plan will unravel the mechanisms by which anti-FimH antibodies may function to prevent UTIs by directly blocking bladder binding and indirectly by interfering with UPEC GIT colonization. These results will inform the rational targeting of the uropathogens that affect millions of people with rUTIs. In addition, our approach enables the rapid generation of anti-UPEC human mAbs that can be used for therapeutics and diagnostics.

总结