Project summary/abstract Escherichia coli O157:H7 is a foodborne pathogen most commonly transmitted to humans when fecal material from cattle comes into contact with food, and the food is subsequently uncooked or undercooked. After colonization of the gastrointestinal tract, the organism can elaborate a toxin called Shiga toxin (Stx), which is necessary for the severe symptoms observed in some patients such as haemolytic uremic syndrome. Previous genetic studies identified several features common to highly virulent E. coli O157:H7 strains. For example, such strains often carry the Stx2a allelic variant, and invariably have a type III secretion system called the LEE. Genome analysis has also supported the hypothesis that highly virulence strains fall within defined phylogenetic lineages. More recently, studies from our group and others began to mechanistically describe how members of the gut microbiota may increase Stx2a production. This proposal builds on our preliminary data that suggests there are at least three mechanisms by which non-pathogenic E. coli increase Stx2a production by E. coli O157:H7 during co- culture: 1) through infection of the non-pathogenic strain by the stx2a-converting bacteriophage, described previously by others; 2) through secretion of a small molecule that triggers Stx2a activation; 3) through an undefined mechanism that does not appear to involve the phage or secreted molecules. Here, we propose in Aim 1 complementary genetic and biochemical approaches to identify the molecule secreted by a human commensal isolate designated 0.1229. Our published work demonstrated that toxin amplification driven by mechanism #1 could be recapitulated in a germ-free mouse model, and we will similarly test the hypothesis here that co-infection of mice with 0.1229 and E. coli O157:H7 results in greater virulence. Preliminary data indicates the secreted molecule has the characteristics of a microcin ? it is small (
|Effective start/end date||5/16/18 → 4/30/21|
- National Institute of Allergy and Infectious Diseases: $252,025.00
- National Institute of Allergy and Infectious Diseases: $197,715.00
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