Activation of human TLR4/MD-2 by hypoacylated lipopolysaccharide from a clinical isolate of Burkholderia cenocepacia

Flaviana Di Lorenzo, Łukasz Kubik, Alja Oblak, Nicola Ivan Lorè, Cristina Cigana, Rosa Lanzetta, Michelangelo Parrilli, Mohamad A. Hamad, Anthony De Soyza, Alba Silipo, Roman Jerala, Alessandra Bragonzi, Miguel A. Valvano, Sonsoles Martín-Santamaría, Antonio Molinaro

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Lung infection by Burkholderia species, in particular B. cenocepacia, accelerates tissue damage and increase post-lung transplant mortality in cystic fibrosis patients. Host- microbes interplay largely depends on interactions between pathogen specific molecules and innate immune receptors such as the Toll-like receptor 4 (TLR4), which recognizes the lipid A moiety of the bacterial lipopolysaccharide (LPS). The human TLR4/MD-2 LPS receptor complex is strongly activated by hexa-acylated lipid A and poorly activated by underacylated lipid A. Here, we report that B. cenocepacia LPS strongly activates human TLR4/MD-2 despite its lipid A having only five acyl chains. Further, we show that aminoarabinose residues in lipid A contribute to TLR4-lipid A interactions, and experiments in a mouse model of LPS-induced endotoxic shock confirmed the pro- inflammatory potential of B. cenocepacia penta-acylated lipid A. Molecular modeling, combined with mutagenesis of TLR4-MD2 interactive surfaces, suggests that longer acyl chains and the aminoarabinose residues in the B. cenocepacia lipid A allow exposure of the fifth acyl chain on the surface of MD-2 enabling interactions with TLR4 and its dimerization. Our results provide a molecular model for activation of the human TLR4/MD- 2 complex by penta-acylated lipid A, explaining the ability of hypoacylated B. cenocepacia LPS to promote pro- inflammatory responses associated to the severe pathogenicity of this opportunistic bacterium.
Original languageEnglish
Pages (from-to)21305-21319
Number of pages15
JournalJournal of Biological Chemistry
Issue number35
Publication statusPublished - 09 Jul 2015


  • cystic fibrosis
  • lipopolysaccharide
  • lipid A
  • inflammasome
  • TLR4
  • inflammation
  • endotoxin


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