Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) remains a challenging medical problem. Extensive thrombogenesis, with accompanying fibrinolysis inhibition, precede the earliest indications of renal injury. Trends in thrombogenesis moreover predict the severity of ensuing HUS. Presumably, a massive endothelial injury before renal injury leads to HUS. This injury is amenable to study, and, possibly, to the attenuation of its effects. In this grant, the thrombogenic process in infected children will be studied intensively. Specifically, we will test the hypotheses that thrombogenesis clearly precedes renal injury, and that the rate of fibrin formation on initial assessment of E. coli O157:H7 infections is associated with outcome (Aim 1). To further assess the coagulation lesion, we will also test the hypotheses that net interval accumulation of fibrin between the first and second day of observation predicts outcome of this infection, and that time-dependent changes in prothrombotic kinetics underlie the pathophysiologic cascade leading to the development of HUS (Aim 2). We will also use our unique population to test the hypotheses that (a) the degree of activation of the complement system predicts outcome in children with E. coli O157:H7 infection, and (b) one or more factor H gene polymorphisms is associated with this outcome (Aim 3). Finally, because the endothelial cell is likely to be critical in the evolution of HUS, we will test the hypothesis that differences between the concentration of circulating endothelial cells in infected children predict outcome. We shall also test the subsidiary hypothesis that these cells express proteins plausibly related to their in situ injury or activation (Aim 4). A unique network has been assembled to identify children at risk of developing HUS an average of three days before HUS develops. This is an inadequately studied, but absolutely appropriate, model for toxin-related HUS. This network will be amalgamated with investigative expertise in the fields of coagulation assessment, complement pathophysiology and genetics, and endothelial cell biology. The project seeks a more complete understanding of the cascade leading to HUS, and, with this knowledge, the successful interdiction of this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052081-10
Application #
6789956
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Hamilton, Frank A
Project Start
2003-02-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
10
Fiscal Year
2004
Total Cost
$374,147
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Page, Andrea V; Tarr, Phillip I; Watkins, Sandra L et al. (2013) Dysregulation of angiopoietin 1 and 2 in Escherichia coli O157:H7 infection and the hemolytic-uremic syndrome. J Infect Dis 208:929-33
Wong, Craig S; Mooney, Jody C; Brandt, John R et al. (2012) Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis 55:33-41
Leopold, Shana R; Shaikh, Nurmohammad; Tarr, Phillip I (2010) Further evidence of constrained radiation in the evolution of pathogenic Escherichia coli O157:H7. Infect Genet Evol 10:1282-5
Laiko, Marina; Murtazina, Rakhilya; Malyukova, Irina et al. (2010) Shiga toxin 1 interaction with enterocytes causes apical protein mistargeting through the depletion of intracellular galectin-3. Exp Cell Res 316:657-66
Besser, Thomas E; Shaikh, Nurmohammad; Holt, Nicholas J et al. (2007) Greater diversity of Shiga toxin-encoding bacteriophage insertion sites among Escherichia coli O157:H7 isolates from cattle than in those from humans. Appl Environ Microbiol 73:671-9
Kudva, Indira T; Krastins, Bryan; Sheng, Haiqing et al. (2006) Proteomics-based expression library screening (PELS): a novel method for rapidly defining microbial immunoproteomes. Mol Cell Proteomics 5:1514-9
Stahl, Anne-lie; Svensson, Majlis; Morgelin, Matthias et al. (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108:167-76
Rashid, Rebecca A; Tabata, Tami A; Oatley, Melissa J et al. (2006) Expression of putative virulence factors of Escherichia coli O157:H7 differs in bovine and human infections. Infect Immun 74:4142-8
Tarr, Phillip I; Gordon, Carrie A; Chandler, Wayne L (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073-86
John, Manohar; Kudva, Indira T; Griffin, Robert W et al. (2005) Use of in vivo-induced antigen technology for identification of Escherichia coli O157:H7 proteins expressed during human infection. Infect Immun 73:2665-79

Showing the most recent 10 out of 23 publications