E. coli ST131 and Intestinal Colonization

描述(由申请人提供)： 在过去的十年里，美国出现了一种单一的大肠杆菌菌株，命名为序列型131(ST131)，成为临床实验室中最常见的单一大肠杆菌菌株，也是导致大多数多重耐药大肠杆菌感染的原因，特别是在退伍军人中。到目前为止，ST131疫情几乎只在临床一级得到确认。事实上，ST131已经造成了大量的感染，其中一些已经非常严重、侵袭性、持续性和/或问题复发。然而，多条证据表明，这种相当明显的临床流行的底物是一种看不见的、但更广泛的涉及ST131的肠道定植和传播流行病，由此ST131在人群中传播，为在被定植的宿主中零星感染ST131奠定了基础。ST131临床流行的有效管理将需要关注这一潜在的肠道定植流行。因此，最重要的研究问题是(I)大肠杆菌ST131作为人类肠道定殖者的程度，特别是在退伍军人中，这可能是ST131‘S最近作为一种播散性多药耐药病原体爆炸性出现的基础，以及(Ii)抗ST131的疫苗是否可以阻止这一过程。因此，该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殖者，ST131比其他氟喹诺酮耐药大肠杆菌(FQREC)更常见，并与特定的宿主特征和暴露有关。目的1：与其他FQREC相比，确定ST131在退伍军人及其家庭接触者中作为肠道定殖者的程度和危险因素。假设2：ST131的宿主定植和/或传播能力比其他耐药大肠杆菌更强。具体地说，它是更易传播的宿主对宿主(这与特定的宿主特征有关)，一旦存在，往往会比其他肠道大肠杆菌竞争更激烈，持续时间更长。目的2：与其他耐药大肠埃希菌比较，评估ST131的S定植新宿主、在宿主间传播、在定植宿主中持续和获得肠道优势的能力，并识别相关的危险因素。假设3：用ST131衍生的抗原免疫小鼠可以产生宿主粘膜IgA免疫反应，该免疫反应能保护小鼠免受ST131挑战菌株的肠道定植。目的3.1：确定小鼠对ST131疫苗株产生强烈肠道IgA反应的免疫条件。目的3.2：在人源化的小鼠模型上，评估这种免疫对ST131挑战株实验性肠道定植的影响。

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.