Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Host-microbe 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

Activation of human TLR4/MD-2 by hypoacylated lipopolysaccharide from a clinical isolate of Burkholderia cenocepacia / DI LORENZO, Flaviana; Kubik, Ł; Oblak, A; Lorè, Ni; Cigana, C; Lanzetta, Rosa; Parrilli, Michelangelo; Hamad, Ma; De Soyza, A; Silipo, Alba; Jerala, R; Bragonzi, A; Valvano, Ma; Martín Santamaría, S; Molinaro, Antonio. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 290:35(2015), pp. 21305-21319. [10.1074/jbc.M115.649087]

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

DI LORENZO, FLAVIANA;LANZETTA, ROSA;PARRILLI, MICHELANGELO;SILIPO, ALBA;MOLINARO, ANTONIO
2015

Abstract

Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Host-microbe 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
2015
Activation of human TLR4/MD-2 by hypoacylated lipopolysaccharide from a clinical isolate of Burkholderia cenocepacia / DI LORENZO, Flaviana; Kubik, Ł; Oblak, A; Lorè, Ni; Cigana, C; Lanzetta, Rosa; Parrilli, Michelangelo; Hamad, Ma; De Soyza, A; Silipo, Alba; Jerala, R; Bragonzi, A; Valvano, Ma; Martín Santamaría, S; Molinaro, Antonio. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 290:35(2015), pp. 21305-21319. [10.1074/jbc.M115.649087]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/609492
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