Human L-ficolin recognizes phosphocholine moieties of pneumococcal teichoic acid

J Immunol. 2014 Dec 1;193(11):5699-708. doi: 10.4049/jimmunol.1400127. Epub 2014 Oct 24.

Abstract

Human L-ficolin is a soluble protein of the innate immune system able to sense pathogens through its fibrinogen (FBG) recognition domains and to trigger activation of the lectin complement pathway through associated serine proteases. L-Ficolin has been previously shown to recognize pneumococcal clinical isolates, but its ligands and especially its molecular specificity remain to be identified. Using solid-phase binding assays, serum and recombinant L-ficolins were shown to interact with serotype 2 pneumococcal strain D39 and its unencapsulated R6 derivative. Incubation of both strains with serum triggered complement activation, as measured by C4b and C3b deposition, which was decreased by using ficolin-depleted serum. Recombinant L-ficolin and its FBG-like recognition domain bound to isolated pneumococcal cell wall extracts, whereas binding to cell walls depleted of teichoic acid (TA) was decreased. Both proteins were also shown to interact with two synthetic TA compounds, each comprising part structures of the complete lipoteichoic acid molecule with two PCho residues. Competition studies and direct interaction measurements by surface plasmon resonance identified PCho as a novel L-ficolin ligand. Structural analysis of complexes of the FBG domain of L-ficolin and PCho revealed that the phosphate moiety interacts with amino acids previously shown to define an acetyl binding site. Consequently, binding of L-ficolin to immobilized acetylated BSA was inhibited by PCho and synthetic TA. Binding of serum L-ficolin to immobilized synthetic TA and PCho-conjugated BSA triggered activation of the lectin complement pathway, thus further supporting the hypothesis of L-ficolin involvement in host antipneumococcal defense.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Wall / metabolism
  • Complement Activation
  • Complement C3b / metabolism
  • Complement C4b / metabolism
  • Fibrinogen / genetics
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate
  • Lectins / genetics
  • Lectins / metabolism*
  • Phosphorylcholine / chemistry
  • Pneumococcal Infections / immunology*
  • Protein Binding
  • Protein Structure, Tertiary / genetics
  • Streptococcus pneumoniae / immunology
  • Streptococcus pneumoniae / metabolism*
  • Surface Plasmon Resonance
  • Teichoic Acids / chemistry
  • Teichoic Acids / metabolism*

Substances

  • Lectins
  • Teichoic Acids
  • ficolin
  • Phosphorylcholine
  • Complement C3b
  • Complement C4b
  • Fibrinogen

Associated data

  • PDB/4NYT