Type 1 fimbrial variation in E coil 018 k1 h7 virulence

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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.