The Shiga toxin (Stx)-producing Escherichia coli (STEC) serotype 0157:H7 is the most common infectious cause of bloody diarrhea, or hemorrhagic colitis (HC), in the U.S. with an estimated incidence of 63,153 cases per annum. Moreover, the hemolytic uremic syndrome (HUS), a sequela of STEC infection, is the most frequent basis for acute kidney failure in U.S. children. In addition, 0157;H7 infection is the leading cause of death in children aged 0-4 years from bacterial infections acquired through food. STEC may produce Stx1 and/or Stx2 and/or a variant of Stx2 (Stx2c and Stx2dact are the most important subtypes associated with human disease). Due to the potential severity of STEC infection, the very low 50% infectious dose, and the easy transmissibility from person to person, 0157:H7 is considered a category B biological threat by the CDC. Eariier this year, a large outbreak with more than 4000 illnesses and 800 cases of HUS occurred in Germany;the outbreak was caused by a ?. coli O104:H4 strain that makes Stx2. The O104:H4 isolate from the outbreak is an enteroaggregative E. coli (EAEC) strain that acquired the phage that carries sfx2, and, as such, can also be considered an STEC. The long-term goals of this project are to define at the molecular, cellular, and whole animal levels the pathogenic mechanisms by which STEC cause disease and to test strategies to prevent and treat these illnesses.
The specific aims are to: 1) examine the relative role(s) of Stx2 and Stx2c in 0157:H7 colonization and in toxicity for mice;2) investigate the mechanisms of enhanced toxicity of elastase-treated (ET)-Stx2dact;3) evaluate the role of diet in host (mouse) response to STEC;and 4) determine the transmissibility of the phage that carries stX2 in O104:H4 with or without ciprofloxacin (cpx) and the impact of cpx treatment on O104:H4 disease.

Public Health Relevance

STEC has a very low 50% infectious dose, can spread easily from person to person, and causes potentially lifethreatening sequelae after infection. As an outcome of this project, we will further delineate the steps by which this pathogen causes disease, which, in turn, may facilitate the creation of more targeted strategies to interfere with the infectious and intoxication processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI020148-32
Application #
8640867
Study Section
Special Emphasis Panel (NSS)
Program Officer
Baqar, Shahida
Project Start
1983-08-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
32
Fiscal Year
2014
Total Cost
$379,781
Indirect Cost
$129,781
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Russo, Lisa M; Melton-Celsa, Angela R; O'Brien, Alison D (2016) Shiga Toxin (Stx) Type 1a Reduces the Oral Toxicity of Stx Type 2a. J Infect Dis 213:1271-9
Melton-Celsa, Angela R; Carvalho, H M; Thuning-Roberson, Claire et al. (2015) Protective efficacy and pharmacokinetics of human/mouse chimeric anti-Stx1 and anti-Stx2 antibodies in mice. Clin Vaccine Immunol 22:448-55
Boisen, Nadia; Melton-Celsa, Angela R; Scheutz, Flemming et al. (2015) Shiga toxin 2a and Enteroaggregative Escherichia coli--a deadly combination. Gut Microbes 6:272-8
Melton-Celsa, Angela R; O'Brien, Alison D; Feng, Peter C H (2015) Virulence Potential of Activatable Shiga Toxin 2d-Producing Escherichia coli Isolates from Fresh Produce. J Food Prot 78:2085-8
Bunger, Joshua C; Melton-Celsa, Angela R; Maynard, Ernest L et al. (2015) Reduced Toxicity of Shiga Toxin (Stx) Type 2c in Mice Compared to Stx2d Is Associated with Instability of Stx2c Holotoxin. Toxins (Basel) 7:2306-20
Russo, Lisa M; Abdeltawab, Nourtan F; O'Brien, Alison D et al. (2015) Mapping of genetic loci that modulate differential colonization by Escherichia coli O157:H7 TUV86-2 in advanced recombinant inbred BXD mice. BMC Genomics 16:947
Russo, Lisa M; Melton-Celsa, Angela R; Smith, Michael J et al. (2014) Comparisons of native Shiga toxins (Stxs) type 1 and 2 with chimeric toxins indicate that the source of the binding subunit dictates degree of toxicity. PLoS One 9:e93463
Boisen, Nadia; Hansen, Anne-Marie; Melton-Celsa, Angela R et al. (2014) The presence of the pAA plasmid in the German O104:H4 Shiga toxin type 2a (Stx2a)-producing enteroaggregative Escherichia coli strain promotes the translocation of Stx2a across an epithelial cell monolayer. J Infect Dis 210:1909-19
Melton-Celsa, Angela R (2014) Shiga Toxin (Stx) Classification, Structure, and Function. Microbiol Spectr 2:EHEC-0024-2013
Russo, L M; Melton-Celsa, A R; Smith, M A et al. (2014) Oral intoxication of mice with Shiga toxin type 2a (Stx2a) and protection by anti-Stx2a monoclonal antibody 11E10. Infect Immun 82:1213-21

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