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Activation of Human Toll-like Receptor 4 (TLR4)center dot Myeloid Differentiation Factor 2 (MD-2) by Hypoacylated Lipopolysaccharide from a Clinical Isolate of Burkholderia cenocepacia

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.

Publication metadata

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.


DOI: 10.1074/jbc.M115.649087


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Funder referenceFunder name
Airbus Military research contract
Cystic Fibrosis Canada
European structural funds
Slovenian Research Agency
Centre of Excellence NMR - Future Innovation for Sustainable Technologies
Financial and Fiscal Commission grant
Higher Education Funding Council of England
BM1003European Cooperation in Science and Technology Actions
CM1102European Cooperation in Science and Technology Actions
CTQ2011-22724Spanish Ministry of Economy and Competitiveness
H2020-MSCA-ITN-2014-ETN TOLLerantMarie Curie Initial Training Networks (ITN) GLYCOPHARM
PC13/2012Universidad CEU San Pablo
PC14/2011Universidad CEU San Pablo
PITN-GA-2012-317297Marie Curie Initial Training Networks (ITN) GLYCOPHARM