title: Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells.
abstract: Gastrointestinal infection with Shiga toxins producing enterohemorrhagic Escherichia coli causes the spectrum of gastrointestinal and systemic complications, including hemorrhagic colitis and hemolytic uremic syndrome, which is fatal in ∼10% of patients. However, the molecular mechanisms of Stx endocytosis by enterocytes and the toxins cross the intestinal epithelium are largely uncharacterized. We have studied Shiga toxin 1 entry into enterohemorrhagic E. coli-infected intestinal epithelial cells and found that bacteria stimulate Shiga toxin 1 macropinocytosis through actin remodeling. This enterohemorrhagic E. coli-caused macropinocytosis occurs through a nonmuscle myosin II and cell division control 42 (Cdc42)-dependent mechanism. Macropinocytosis of Shiga toxin 1 is followed by its transcytosis to the basolateral environment, a step that is necessary for its systemic spread. Inhibition of Shiga toxin 1 macropinocytosis significantly decreases toxin uptake by intestinal epithelial cells and in this way provides an attractive, antibiotic-independent strategy for prevention of the harmful consequences of enterohemorrhagic E. coli infection.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Lukyanenko
authors.forename: Irina
authors.initials: I
authors.lastname: Malyukova
authors.forename: Ann
authors.initials: A
authors.lastname: Hubbard
authors.forename: Michael
authors.initials: M
authors.lastname: Delannoy
authors.forename: Edgar
authors.initials: E
authors.lastname: Boedeker
authors.forename: Chengru
authors.initials: C
authors.lastname: Zhu
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.forename: Olga
authors.initials: O
authors.lastname: Kovbasnjuk
mesh_terms: D000199:Actins / Q000378:metabolism; D002460:Cell Line; D003106:Colon / Q000378:metabolism / Q000382:microbiology; D054324:Enterohemorrhagic Escherichia coli; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D024462:Myosin Type II / Q000378:metabolism; D010873:Pinocytosis; D022622:Shiga Toxin 1 / Q000378:metabolism*; D057900:Transcytosis; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D022622:Shiga Toxin 1; D024462:Myosin Type II; D020764:cdc42 GTP-Binding Protein