E. coli ST131 and Intestinal Colonization

大肠杆菌 ST131 和肠道定植

• 批准号: 8644347
• 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/8644347
• 关键词: Acute; Address; Antigens; Antimicrobial Resistance; Attention; Bacteremia; Biopsy; 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; Prostate; Recurrence; Resistance; Risk Factors; Site; Staging; Testing; Urinary tract infection; Ursidae Family; Vaccines; Veterans; base; burden of illness; density; fluoroquinolone resistance; member; modifiable risk; mortality; mouse model; pathogen; 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（指定为131型序列（ST131）），是临床实验室中最常见的大肠杆菌菌株，是最具多药的大肠杆菌感染的原因，尤其是在退伍军人中。迄今为止，ST131流行病几乎完全在临床水平上被识别。确实，ST131引起了大量感染，其中一些感染非常严重，侵入性，持久性和/或有问题的反复发作。但是，多种证据表明，这种相当明显的临床流行的底物是一种看不见的，但更广泛的肠道定植和传播的流行，涉及ST131，ST131在人群中传播，为群体宿主中零星的ST131感染奠定了阶段。 ST131临床流行的有效管理将需要注意这种潜在的肠道定植流行。因此，整个研究问题是（i）大肠杆菌ST131作为人类肠道菌落的范围，尤其是在退伍军人中，这可能是ST131最近的爆炸性出现的基础，作为传播的多种耐药性病原体，以及（ii）抗ST131疫苗是否可以阻止此过程。因此，通过实现以下特定目的，该项目将检验以下假设：假设1：作为退伍军人及其家庭接触的肠结构剂，ST131比其他耐氟喹诺酮类药物（FQREC）更为普遍，并且与特定的宿主特征和经验相关联。 目标1：与其他FQREC相比，将ST131的程度和风险因素定义为退伍军人及其家庭接触的肠道菌落器的程度和危险因素。假设2：ST131比其他抗菌大肠杆菌更有能力宿主定植和/或传播。具体而言，它是更可传播的宿主到hos（与特定的宿主特征相关），并且一旦存在就倾向于超出竞争和持续时间比其他肠道大肠杆菌更长。 AIM 2：评估ST131与其他耐药大肠杆菌相比，ST131具有定居新宿主，在宿主之间传播，持续存在的宿主并实现肠道优势的能力，并确定相关的风险因素。假设3：用ST131衍生的抗原的小鼠免疫可以产生宿主粘膜IgA免疫反应，可防止ST131挑战菌株防止肠道定植。 AIM 3.1：定义免疫条件，在小鼠对ST131疫苗菌株中产生强肠IgA反应。 AIM 3.2：在人源化小鼠模型中使用ST131挑战菌株评估这种免疫对实验性肠道定植的影响。