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Lookup NU author(s): Professor Anthony De SoyzaORCiD
Background: The Burkholderia cenocepacia lipid A is hypoacylated. Results: Aminoarabinose residues in lipid A contribute to Burkholderia lipid A binding to the TLR4MD-2 complex. Conclusion: A novel mode of Burkholderia lipopolysaccharide-TLR4MD-2 interactions promotes inflammation. Significance: Modifications of the lipid A structure enhance proinflammatory responses of hypoacylated lipopolysaccharide.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 TLR4myeloid 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 TLR4MD-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 TLR4MD-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.
Author(s): Di Lorenzo F, Kubik L, Oblak A, Lore NI, Cigana C, Lanzetta R, Parrilli M, Hamad MA, De Soyza A, Silipo A, Jerala R, Bragonzi A, Valvano MA, Martin-Santamaria S, Molinaro A
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Year: 2015
Volume: 290
Issue: 35
Pages: 21305-21319
Print publication date: 28/08/2015
Online publication date: 09/07/2015
Acceptance date: 01/01/1900
Date deposited: 08/02/2017
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
URL: http://dx.doi.org/10.1074/jbc.M115.649087
DOI: 10.1074/jbc.M115.649087
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