Abstract

The hypothesis proposed in grant R01 DK42029 stated that renal interstitial attachment of Dr adhesin bearing Escherichia coli creates structural basis for development of chronic interstitial nephritis. Exploration of consequences of Dr-adhesin Dr-tissue-ligand interaction resulted in the development of an experimental model of ascending chronic pyelonephritis (ChP) that fulfills histological requirements for human ChP. In this project, the investigators will attempt to understand the molecular mechanisms involved in and to prevent the development of ChP. They will attempt the following projects. Map receptor-binding epitopes on short consensus repeat-3 (SCR-3) domain of decay accelerating factor (DAF) for Dr fimbriae. (a) Map Dr binding epitopes on DAF-SCR-3 by synthetic peptides by competitive inhibition. (b) Map Dr binding epitopes on DAF-SCR-3 by antipeptide antibodies. (c) Replace single amino acids within the SCR-3 region using site-directed mutagenesis. (d) Test in vitro attachment of BN406 on Chinese hamster ovary (CHO) cells that express constructed DAF (SCR-3) mutants. (2) Map functional regions within the dra operon necessary for interstitial colonization and developing ChP on a mouse C3H/HeJ in vivo model. (a) Characterize the nucleotide sequence of the draA, draB. draC, draD, and draE mutants on a ChP model to dissect involvement of adhesive, and renal interstitial tropism properties in the development of ChP. (c) Examine virulence of draA substitution mutants defective in type-IV collagen binding on a ChP mouse model. (d) Study route and kinetics of dra mutants spread leading to interstitial colonization on a SCID mouse model. (3) Test the effect of vaccination with recombinant Dr adhesin on development of ChP in C3H/HeJ mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042029-07
Application #
6124857
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Nyberg, Leroy M
Project Start
1992-02-01
Project End
2000-11-30
Budget Start
1999-12-15
Budget End
2000-11-30
Support Year
7
Fiscal Year
2000
Total Cost
$163,104
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

Sledzi?ska, A; Mielech, A; Krawczyk, B et al. (2011) Fatal sepsis in a pregnant woman with pyelonephritis caused by Escherichia coli bearing Dr and P adhesins: diagnosis based on postmortem strain genotyping. BJOG 118:266-9
Wroblewska-Seniuk, Katarzyna; Nowicki, Stella; Le Bouguénec, Chantal et al. (2011) Maternal/fetal mortality and fetal growth restriction: role of nitric oxide and virulence factors in intrauterine infection in rats. Am J Obstet Gynecol 205:83.e1-7
Nowicki, B; Sledzinska, A; Samet, A et al. (2011) Pathogenesis of gestational urinary tract infection: urinary obstruction versus immune adaptation and microbial virulence. BJOG 118:109-12
Pawelczyk, Edyta; Nowicki, Bogdan J; Izban, Michael G et al. (2010) Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes. BMC Pregnancy Childbirth 10:66
Nowicki, Stella; Izban, Michael G; Pawelczyk, Edyta et al. (2009) Preterm labor: CD55 in maternal blood leukocytes. Am J Reprod Immunol 61:360-7
Rice, J C; Peng, T; Kuo, Y-F et al. (2006) Renal allograft injury is associated with urinary tract infection caused by Escherichia coli bearing adherence factors. Am J Transplant 6:2375-83
Rice, James C; Peng, Tao; Spence, Jeff S et al. (2005) Pyelonephritic Escherichia coli expressing P fimbriae decrease immune response of the mouse kidney. J Am Soc Nephrol 16:3583-91
Das, Margaret; Hart-Van Tassell, Audrey; Urvil, Petri T et al. (2005) Hydrophilic domain II of Escherichia coli Dr fimbriae facilitates cell invasion. Infect Immun 73:6119-26
Selvarangan, Rangaraj; Goluszko, Pawel; Singhal, Jyotsana et al. (2004) Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence. Infect Immun 72:4827-35
Johnson, James R; Stell, Adam L; O'Bryan, Timothy T et al. (2002) Global molecular epidemiology of the O15:K52:H1 extraintestinal pathogenic Escherichia coli clonal group: evidence of distribution beyond Europe. J Clin Microbiol 40:1913-23

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