Abstract
Escherichia coli O157∶H7 is a human enteric pathogen that causes hemorrhagic colitis which can progress to hemolytic uremic syndrome, a severe kidney disease with immune involvement. During infection, E. coli O157∶H7 secretes StcE, a metalloprotease that promotes the formation of attaching and effacing lesions and inhibits the complement cascade via cleavage of mucin-type glycoproteins. We found that StcE cleaved the mucin-like, immune cell-restricted glycoproteins CD43 and CD45 on the neutrophil surface and altered neutrophil function. Treatment of human neutrophils with StcE led to increased respiratory burst production and increased cell adhesion. StcE-treated neutrophils exhibited an elongated morphology with defective rear detachment and impaired migration, suggesting that removal of the anti-adhesive capability of CD43 by StcE impairs rear release. Use of zebrafish embryos to model neutrophil migration revealed that StcE induced neutrophil retention in the fin after tissue wounding, suggesting that StcE modulates neutrophil-mediated inflammation in vivo. Neutrophils are crucial innate effectors of the antibacterial immune response and can contribute to severe complications caused by infection with E. coli O157∶H7. Our data suggest that the StcE mucinase can play an immunomodulatory role by directly altering neutrophil function during infection. StcE may contribute to inflammation and tissue destruction by mediating inappropriate neutrophil adhesion and activation.
Highlights
Enterohemorrhagic Escherichia coli (EHEC) of serogroup O157:H7 is an emerging human diarrheal pathogen associated with numerous food-borne outbreaks in the U.S Infection of the colon by EHEC causes mild diarrhea that proceeds to bloody colitis and can be acquired following ingestion of fewer than 100 organisms [1]
Enterohemorrhagic Escherichia coli (EHEC) poses a significant threat to the U.S food supply, causing foodborne gastrointestinal disease in humans that can progress to hemolytic uremic syndrome (HUS), a potentially fatal kidney disease
We define mucinase activity toward glycoproteins on the surface of human neutrophils and find that StcE alters neutrophil activity by interacting with these proteins
Summary
Enterohemorrhagic Escherichia coli (EHEC) of serogroup O157:H7 is an emerging human diarrheal pathogen associated with numerous food-borne outbreaks in the U.S Infection of the colon by EHEC causes mild diarrhea that proceeds to bloody colitis and can be acquired following ingestion of fewer than 100 organisms [1]. In 15% of childhood cases, EHEC gastroenteritis progresses to the more serious hemolytic uremic syndrome (HUS), characterized by red blood cell fragmentation, low platelet count, and acute renal failure. EHEC virulence factors include the locus of enterocyte effacement, which confers the ability to form attaching and effacing lesions, and the phage-encoded Shiga toxin, which causes termination of protein synthesis in the microvascular endothelium leading to cell death and tissue destruction [3]. Models of EHECinduced diarrhea in rabbits or injection of purified components leading to HUS-like symptoms in mice and baboons have been described, no model exists that follows the natural progression from EHEC infection to development of HUS [4,5,6]
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