title: Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7.
abstract: Toll-like receptors (TLRs) are key factors of innate immunity that detect pathogen invasion and trigger a host response. TLR4 can mediate a response through adaptor molecules, MyD88 or TRIF. In the present study, streptomycin-treated MyD88(-/-), Tlr4(-/-), Trif (Lps2/Lps2), and C57BL/6 wild-type (WT) mice were infected with either Shiga toxin (Stx)-producing or non-producing Escherichia coli O157:H7. Moderate to severe clinical signs of disease developed in MyD88(-/-) (n = 21/21), Tlr4(-/-) (n = 12/16), Trif (Lps2/Lps2) (n = 7/15) and WT mice (n = 6/20) infected with Stx-producing E. coli O157:H7 but not in mice inoculated with the Stx non-producing strain (n = 0/54, P < 0.001). MyD88(-/-) mice infected with Stx-producing E. coli O157:H7 developed the most severe disease and had the highest bacterial burden. Hematological analysis of sick MyD88(-/-) mice showed reduced red blood cell counts and reticulocytosis, suggesting hemolysis. Thrombocytopenia developed in MyD88(-/-), Trif (Lps2/Lps2), and WT mice, and creatinine levels were elevated in both MyD88(-/-) and WT mice infected with the Stx-producing strain. Renal histopathology showed evidence of glomerular capillary congestion, tubular desquamation, and fibrinogen deposition, and intestinal histopathology showed mucosal injury, edema, and inflammation in sick mice. Administration of purified Stx2 to MyD88(-/-) and WT mice led to severe disease in both groups, suggesting that MyD88(-/-) mice are not more sensitive to Stx than WT mice. As MyD88(-/-) mice developed the most severe disease hematological and pathological changes, the results suggest that dysfunctional innate immune responses via MyD88 enhanced Stx-induced disease.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund.
authors.forename: Carla
authors.initials: C
authors.lastname: Calderon Toledo
authors.forename: Trisha Jayne
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Majlis
authors.initials: M
authors.lastname: Svensson
authors.forename: Ramesh
authors.initials: R
authors.lastname: Tati
authors.forename: Hans
authors.initials: H
authors.lastname: Fischer
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000740:Anemia / Q000382:microbiology; D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight; D015169:Colony Count, Microbial; D003404:Creatinine / Q000097:blood; D004927:Escherichia coli Infections / Q000097:blood / Q000382:microbiology* / Q000503:physiopathology; D019453:Escherichia coli O157 / Q000254:growth & development / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism; D006461:Hemolysis; D007113:Immunity, Innate; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D007668:Kidney / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000378:metabolism; D010976:Platelet Count; D022621:Shiga Toxin / Q000276:immunology* / Q000302:isolation & purification; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D022621:Shiga Toxin; D005340:Fibrinogen; D003404:Creatinine