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Use of Shigella flexneri to Study Autophagy-Cytoskeleton Interactions
Published on: September 9, 2014
Inhibition of Shigella flexneri-induced transepithelial migration of polymorphonuclear leucocytes by cadaverine
B A McCormick1, M I Fernandez, A M Siber
1Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital-East, Charlestown 02129, USA. mccormic@helix.mgh.harvard.edu
Abstract:
Dysentery caused by Shigella species is characterized by infiltration of polymorphonuclear leucocytes (PMNs) into the colonic mucosa. Shigella spp. evolved into pathogens by the acquisition of virulence genes and by the deletion of 'antivirulence' genes detrimental to its pathogenic lifestyle. An example is cadA (encoding lysine decarboxylase), which is uniformly absent in Shigella spp., whereas it is present in nearly all isolates of the closely related non-pathogen Escherichia coli. Here, using monolayers of T84 cells to model the human intestinal epithelium, we determined that the introduction of cadA into S. flexneri and the expression of lysine decarboxylase attenuated the bacteria's ability to induce PMN influx across model intestinal epithelium. Such inhibition was caused by cadaverine generated from the decarboxylation of lysine. Cadaverine treatment of model intestinal epithelia specifically inhibited S. flexneri induction of PMN transepithelial migration, while having no effect on the ability of Salmonella or enteropathogenic E. coli (EPEC) to induce PMN migration. These observations not only provide insight into mechanisms of S. flexneri pathogen evolution and pathogenesis, but also suggest a potential for the use of cadaverine in the treatment of dysentery.
Insights
Shigella bacteria cause dysentery by inducing inflammatory cell infiltration. Introducing a specific gene (cadA) producing cadaverine reduced this inflammation, suggesting cadaverine as a potential dysentery treatment.
Area of Science:
- Microbiology
- Pathogenesis
- Molecular Biology
Background:
- Dysentery, caused by Shigella species, involves polymorphonuclear leucocytes (PMNs) infiltrating the colonic mucosa.
- Shigella pathogenesis is linked to acquiring virulence genes and losing 'antivirulence' genes, like cadA, present in non-pathogenic E. coli.
Purpose of the Study:
- To investigate the role of the cadA gene and its product, lysine decarboxylase, in Shigella pathogenesis.
- To explore the potential of cadaverine as a therapeutic agent for dysentery.
Main Methods:
- Utilized T84 cell monolayers to model the human intestinal epithelium.
- Introduced the cadA gene into S. flexneri and assessed its effect on PMN influx.
- Treated model intestinal epithelia with cadaverine to evaluate its impact on PMN migration induced by different bacterial species.
Main Results:
- Expression of lysine decarboxylase in S. flexneri attenuated its ability to induce PMN influx across the intestinal epithelium model.
- Cadaverine, generated from lysine decarboxylation, specifically inhibited S. flexneri-induced PMN transepithelial migration.
- Cadaverine did not affect PMN migration induced by Salmonella or enteropathogenic E. coli (EPEC).
Conclusions:
- The cadA gene and cadaverine production play a role in modulating Shigella pathogenesis by reducing PMN infiltration.
- These findings offer insights into S. flexneri evolution and pathogenesis mechanisms.
- Cadaverine shows potential as a therapeutic agent for treating Shigella-induced dysentery.
