title: Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy.
abstract: Enterohemorrhagic Escherichia coli (EHEC) produce ribosome-inactivating Shiga toxins (Stx1, Stx2) responsible for development of hemolytic uremic syndrome (HUS) and acute kidney injury (AKI). Some patients show complement activation during EHEC infection, raising the possibility of therapeutic targeting of complement for relief. Our juvenile nonhuman primate (Papio baboons) models of endotoxin-free Stx challenge exhibit full spectrum HUS, including thrombocytopenia, hemolytic anemia, and AKI with glomerular thrombotic microangiopathy. There were no significant increases in soluble terminal complement complex (C5b-9) levels after challenge with lethal Stx1 (n = 6) or Stx2 (n = 5) in plasma samples from T0 to euthanasia at 49.5 to 128 hours post-challenge. d-dimer and cell injury markers (HMGB1, histones) confirmed coagulopathy and cell injury. Thus, complement activation is not required for the development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins in these preclinical models, and benefits or risks of complement inhibition should be studied further for this infection.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lee
authors.forename: Chad L
authors.initials: CL
authors.lastname: Mayer
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Leibowitz
authors.forename: D J
authors.initials: DJ
authors.lastname: Stearns-Kurosawa
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kurosawa
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D003167:Complement Activation / Q000502:physiology; D003165:Complement System Proteins / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006463:Hemolytic-Uremic Syndrome / Q000150:complications / Q000209:etiology / Q000276:immunology*; D010215:Papio; D011323:Primates; D022621:Shiga Toxin / Q000494:pharmacology; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity / Q000502:physiology; D057049:Thrombotic Microangiopathies / Q000150:complications / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D022621:Shiga Toxin; D003165:Complement System Proteins