Activation of Human Toll-like receptor 4 (TLR4)·myeloid differentiation factor 2 (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

Research output: Contribution to journalArticle

Abstract

Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Hostmicrobe interplay largely depends on interactions between pathogen-specific molecules and innate immune receptors such as Toll-like receptor 4 (TLR4), which recognizes the lipid A moiety of the bacterial lipopolysaccharide (LPS). The human TLR4·myeloid differentiation factor 2 (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. Furthermore, 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 proinflammatory potential of B. cenocepacia penta-acylated lipid A. Molecular modeling combined with mutagenesis of TLR4-MD-2 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 proinflammatory responses associated with the severe pathogenicity of this opportunistic bacterium.

Original languageEnglish
Pages (from-to)21305-21319
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number35
DOIs
Publication statusPublished - Aug 28 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Di Lorenzo, F., Kubik, Ł., Oblak, A., Lorè, N. I., Cigana, C., Lanzetta, R., Parrilli, M., Hamad, M. A., De Soyza, A., Silipo, A., Jerala, R., Bragonzi, A., Valvano, M. A., Martín-Santamaría, S., & Molinaro, A. (2015). Activation of Human Toll-like receptor 4 (TLR4)·myeloid differentiation factor 2 (MD-2) by hypoacylated lipopolysaccharide from a clinical isolate of Burkholderia cenocepacia. Journal of Biological Chemistry, 290(35), 21305-21319. https://doi.org/10.1074/jbc.M115.649087