title: Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins.
abstract: Pathogenic microbes have evolved sophisticated molecular strategies to subvert host defenses. Here we show that virulent bacteria interfere directly with Toll-like receptor (TLR) function by secreting inhibitory homologs of the Toll/interleukin-1 receptor (TIR) domain. Genes encoding TIR domain containing-proteins (Tcps) were identified in Escherichia coli CFT073 (TcpC) and Brucella melitensis (TcpB). We found that TcpC is common in the most virulent uropathogenic E. coli strains and promotes bacterial survival and kidney pathology in vivo. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1, and we show that the Tcps impede TLR signaling through the myeloid differentiation factor 88 (MyD88) adaptor protein, owing to direct binding of Tcps to MyD88. Tcps represent a new class of virulence factors that act by inhibiting TLR- and MyD88-specific signaling, thus suppressing innate immunity and increasing virulence.
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, D-81675 München, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Cirl
authors.forename: Andreas
authors.initials: A
authors.lastname: Wieser
authors.forename: Manisha
authors.initials: M
authors.lastname: Yadav
authors.forename: Susanne
authors.initials: S
authors.lastname: Duerr
authors.forename: Sören
authors.initials: S
authors.lastname: Schubert
authors.forename: Hans
authors.initials: H
authors.lastname: Fischer
authors.forename: Dominik
authors.initials: D
authors.lastname: Stappert
authors.forename: Nina
authors.initials: N
authors.lastname: Wantia
authors.forename: Nuria
authors.initials: N
authors.lastname: Rodriguez
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
authors.forename: Thomas
authors.initials: T
authors.lastname: Miethke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002002:Brucella / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D002460:Cell Line; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D004927:Escherichia coli Infections / Q000209:etiology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005798:Genes, Bacterial; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011704:Pyelonephritis / Q000209:etiology; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014552:Urinary Tract Infections / Q000209:etiology; D014774:Virulence; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D029968:Escherichia coli Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C549538:TcpC protein, E coli; D051193:Toll-Like Receptors; D037521:Virulence Factors