Abstract
Shiga toxin-producing Escherichia coli O157:H7 is a virulent strain causing severe gastrointestinal infection, hemolytic uremic syndrome and death. To date there are no specific therapies to reduce progression of disease. Here we investigated the effect of pooled immunoglobulins (IgG) on the course of disease in a mouse model of intragastric E. coli O157:H7 inoculation. Intraperitoneal administration of murine IgG on day 3, or both on day 3 and 6, post-inoculation improved survival and decreased intestinal and renal pathology. When given on both day 3 and 6 post-inoculation IgG treatment also improved kidney function in infected mice. Murine and human commercially available IgG preparations bound to proteins in culture filtrates from E. coli O157:H7. Bound proteins were extracted from membranes and peptide sequences were identified by mass spectrometry. The findings showed that murine and human IgG bound to E. coli extracellular serine protease P (EspP) in the culture filtrate, via the IgG Fc domain. These results were confirmed using purified recombinant EspP and comparing culture filtrates from the wild-type E. coli O157:H7 strain to a deletion mutant lacking espP. Culture filtrates from wild-type E. coli O157:H7 exhibited enzymatic activity, specifically associated with the presence of EspP and demonstrated as pepsin cleavage, which was reduced in the presence of murine and human IgG. EspP is a virulence factor previously shown to promote colonic cell injury and the uptake of Shiga toxin by intestinal cells. The results presented here suggest that IgG binds to EspP, blocks its enzymatic activity, and protects the host from E. coli O157:H7 infection, even when given post-inoculation.
Highlights
Enterohemorrhagic Escherichia coli (EHEC) is a human pathogen, transmitted via contaminated food and water causing diarrhea and hemorrhagic colitis
A significant difference in survival was found between mice infected with E. coli O157:H7 and treated with immunoglobulin G (IgG) on day 3 and 6 compared to infected and untreated mice, P
Mice infected with E. coli O157:H7 and treated with IgG on day 3 post-inoculation exhibited 80% survival (4/5 mice), compared to infected and untreated mice, P
Summary
Enterohemorrhagic Escherichia coli (EHEC) is a human pathogen, transmitted via contaminated food and water causing diarrhea and hemorrhagic colitis. It is the main cause of hemolytic uremic syndrome (HUS) [1]. Diarrheagenic E. coli secrete serine proteases by means of a type V secretion system, the Serine Protease Autotransporter of Enterobacteriaceae (SPATEs) protein family [10]. These proteases function as enterotoxins thereby causing diarrhea [11]. One such protease in EHEC is extracellular serine protease P (EspP) shown to be important for adherence to bovine intestinal cells [12] and ion transport in human colonoid cells, that could suggest a role in the development of watery diarrhea [11]. EspP cleaves coagulation factor V [14] and complement C3, C3b and C5 [15] showing that it could impact host proteins important for coagulation and complement activation
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