E. coli ST131 and Intestinal Colonization

大肠杆菌 ST131 和肠道定植

• 批准号: 8904313
• 负责人: JAMES R JOHNSON
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904313
• 关键词: Acute; Address; Antigens; Antimicrobial Resistance; Attention; Bacteremia; Carrier State; Characteristics; Clinical; Cystitis; Data; Development; Disease; Drug resistance; Ecology; Epidemic; Escherichia coli; Escherichia coli Infections; Future; Health Benefit; Health Care Costs; Household; Human; Immune response; Immunization; Immunoglobulin A; Individual; Infection; Intervention; Intestines; Laboratories; Modification; Morbidity - disease rate; Multi-Drug Resistance; Mus; Persons; Population; Prevalence; Preventive Intervention; Process; Recurrence; Resistance; Risk Factors; Site; Staging; Testing; Urinary tract infection; Ursidae Family; Vaccines; Veterans; base; burden of illness; density; fluoroquinolone resistance; gut microbiota; member; modifiable risk; mortality; mouse model; multi-drug resistant pathogen; prostate biopsy; prostatitis; public health relevance; resistant strain; response; success; transmission process; vaccine development

DESCRIPTION (provided by applicant): A single Escherichia coli strain, designated sequence type 131 (ST131), has emerged in the U.S. over the past decade as the single most common E. coli strain in clinical laboratories and as the cause of most multidrug- resistant E. coli infection, particularly among veterans. To date, the ST131 epidemic has been recognized almost exclusively at the clinical level. Indeed, ST131 has caused huge numbers of infections, some of which have been strikingly severe, invasive, persistent, and/or problematically recurrent. However, multiple lines of evidence suggest that the substrate for this quite obvious clinical epidemic is an invisible, but much more extensive, epidemic of intestinal colonization and transmission involving ST131, whereby ST131 disseminates within the population, setting the stage for sporadic ST131 infections in colonized hosts. Effective management of the ST131 clinical epidemic will require attention to this underlying intestinal colonization epidemic. Thus, the over-arching study questions are (i) the extent of E. coli ST131 as a human intestinal colonizer, especially among veterans, which likely underlies ST131's recent explosive emergence as a disseminated multidrug- resistant pathogen, and (ii) whether an anti-ST131 vaccine can block this process. Therefore, the project will test the following hypotheses, through accomplishment of the following specific aims: Hypothesis 1: As an intestinal colonizer among veterans and their household contacts, ST131 is more prevalent than other fluoroquinolone-resistant E. coli (FQREC), and is associated with specific host characteristics and exposures. Aim 1: Define the extent of, and risk factors for, ST131 as an intestinal colonizer among veterans and their household contacts, compared with other FQREC. Hypothesis 2: ST131 is more capable of host colonization and/or transmission than are other antimicrobial- resistant E. coli. Specifically, it is more transmissible host-to-hos (which is associated with specific host characteristics), and once present tends to both out-compete and persist longer than other intestinal E. coli. Aim 2: Assess ST131's ability to colonize new hosts, spread among hosts, persist in colonized hosts, and achieve intestinal predominance, compared to other resistant E. coli, and identify associated risk factors. Hypothesis 3: Immunization of mice with ST131-derived antigens can engender a host mucosal IgA immune response that protects against intestinal colonization by an ST131 challenge strain. Aim 3.1: Define immunization conditions that yield strong intestinal IgA responses in mice to an ST131 vaccine strain. Aim 3.2: Assess the effect of such immunization on experimental gut colonization with an ST131 challenge strain in a humanized mouse model.

描述（由申请人提供）： 在过去的十年中，在美国出现了一种单一的大肠杆菌菌株，称为序列型131（ST 131），是最常见的大肠杆菌。大肠埃希菌是临床实验室中最常见的多药耐药大肠埃希菌。大肠杆菌感染，尤其是退伍军人。迄今为止，ST 131流行病几乎完全在临床层面得到了确认。事实上，ST 131已经引起了大量的感染，其中一些是非常严重的，侵入性的，持续性的和/或有问题的复发。然而，多条证据表明，这种相当明显的临床流行病的底物是一种看不见的，但更广泛的，涉及ST 131的肠道定殖和传播的流行病，由此ST 131在人群中传播，为定殖宿主中的散发性ST 131感染奠定了基础。ST 131临床流行病的有效管理需要关注这种潜在的肠道定植流行病。因此，过度研究的问题是：（i）E.大肠杆菌ST 131作为人类肠道定植者，特别是退伍军人，这可能是ST 131最近作为一种传播性多药耐药病原体爆发性出现的基础，以及（ii）抗ST 131疫苗是否可以阻断这一过程。因此，本项目将通过实现以下具体目标来检验以下假设：假设1：作为退伍军人及其家庭接触者中的肠道定植者，ST 131比其他氟喹诺酮类耐药大肠杆菌更普遍。大肠杆菌（Escherichia coli，Escherichia coli，Escherichia rec）的感染，并与特定的宿主特征和暴露有关。 目标1：定义的程度，和风险因素，ST 131作为肠道殖民者之间的退伍军人和他们的家庭接触，与其他CNOREC相比。假设2：ST 131比其他耐药大肠杆菌更能在宿主中定植和/或传播。杆菌特别是，它更容易在宿主间传播（这与特定的宿主特征有关），一旦存在，往往会比其他肠道E。杆菌 目标二：与其他耐药大肠杆菌相比，评估ST 131定殖新宿主、在宿主间传播、在定殖宿主中持续存在以及实现肠道优势的能力。大肠杆菌，并确定相关的风险因素。假设三：用ST 131衍生的抗原免疫小鼠可以产生宿主粘膜伊加免疫应答，其保护免受ST 131攻击菌株的肠定殖。 目的3.1：确定在小鼠中对ST 131疫苗株产生强烈肠道伊加应答的免疫条件。 目的3.2：评估这种免疫对人源化小鼠模型中ST 131攻击株实验性肠道定植的影响。