Type 1 fimbrial variation in E coil 018 k1 h7 virulence

描述（由申请人提供）：大肠杆菌菌株在成年妇女中产生阴道和尿路感染（uti）和新生儿脑膜炎（NBM）的能力导致了对这些重要病原体的“粪便-阴道-泌尿/新生儿”传播途径的研究。产生大多数这些感染的是数量有限的肠外致病性大肠杆菌（ExPEC）克隆，其特点是拥有通过水平转移获得的多种毒力因子（VFs）。虽然没有单一的“经典”VF发生在所有的exic分离株中，但几乎所有的大肠杆菌都表达1型菌毛，黏附丝被证明是肠道和肠外宿主生态位中必不可少的定植因子。由于单核苷酸多态性（snp）能够在1型菌毛粘附素（FimH）的等位基因之间产生不同的功能特性，菌毛的多功能性可能在共生和致病的生活方式之间架起桥梁。

DESCRIPTION (provided by applicant): The ability of E. coli strains to produce vaginal and urinary tract infections (UTIs) in adult women and meningitis in newborns (NBM) has led to study of the "fecal-vaginal-urinary/neonatal" route of transmission of these important pathogens. Producing most of these infections is a limited number of extraintestinal pathogenic E. coli (ExPEC) clones, which are characterized by possession of multiple virulence factors (VFs) that have been acquired by horizontal transfer. While no single "classic" VF occurs in all ExPEC isolates, virtually all E. coli express type 1 fimbriae, adhesive filaments shown to be essential colonization factors in both intestinal and extraintestinal host niches. The versatility of the fimbriae, which may bridge commensal and pathogenic lifestyles, is due to the ability of single nucleotide polymorphisms (SNPs) to produce variant functional properties among alleles of the type 1 fimbrial adhesin, FimH. The O18:K1:H7 serotype constitutes the most prevalent group of ExPEC isolates, causing 15% of E. coli cystitis and 20% of E. coli NBM in the United States. Among O18:K1 :H7 strains, SNPs have determined functional variants of FimH with distinctive binding properties: A62-containing alleles confer shear-independent binding and strong adhesion to monomannose and collagen residues, as well as human bladder epithelial monolayers; S62 alleles confer shear dependent binding, and weak adhesion to these substrates. All North American O18:K1 :H7 strains carry the A62 FimH polymorphism, as well as (UTI- associated VFs) P fimbriae, hemolysin and cnf1, while many European strains carry S62 FimH and none of these VFs. In Specific Aims 1 and 2, we will characterize distinctive properties determined by 018:Kl:H7 FimH allele SNPs, with regard to host strains' ability to: (1) bind and invade human vaginal and bladder epithelium, (2) be bound, ingested, and killed by human neutrophils, and (3) produce UTI in a murine model. In Specific Aim 3, we will analyze a large collection of vaginal E. coli strains to determine prevalence of O18:K1 :H7 among vaginal E. coli O18:K1:H7 isolates will be evaluated with regard to VF carriage as well as sequence of type I fimbrial determinants fimH and fimA. In addition to identifying ongoing serotype evolution, the data will also assist in development of a rapid technique - based on SNPs -for identifying O18:K1 :H7 strains among laboratory isolates. Such a test might ultimately be used to identify women at increased risk of chorioamnionitis and pre-term labor, or of delivering infected newborns. Thus, the work described could lead to reduction in the burden of E. coli disease among mothers and infants. The proposal also describes a detailed plan for the career development of the candidate into an independent clinician scientist, featuring: didactic coursework in bacterial pathogenesis and genomics, regular evaluations by a career advisory committee, and training in the responsible conduct of research.