Inhibition of Shigella flexneri-induced transepithelial migration of polymorphonuclear leucocytes by cadaverine.
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.
McCormick
B A
BA
Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital-East, Charlestown 02129, USA. mccormic@helix.mgh.harvard.edu
Fernandez
M I
MI
Siber
A M
AM
Maurelli
A T
AT
D000199:Actins / Q000378:metabolism; D002103:Cadaverine / Q000378:metabolism / Q000494:pharmacology*; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D016764:Cell Polarity; D048429:Cell Size; D004305:Dose-Response Relationship, Drug; D004403:Dysentery; D004797:Enzyme-Linked Immunosorbent Assay; D019453:Escherichia coli O157 / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000382:microbiology*; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000378:metabolism; D012763:Shigella flexneri / Q000378:metabolism / Q000472:pathogenicity*; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein
D000199:Actins; D016209:Interleukin-8; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002262:Carboxy-Lyases; C021520:lysine decarboxylase; D008239:Lysine; D002103:Cadaverine