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J Biol Chem. 2015 Aug 28;290(35):21305-19. doi: 10.1074/jbc.M115.649087. Epub 2015 Jul 9.

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

Author information

1
From the Departments of Chemical Sciences and Department of Biotechnology, National Institute of Chemistry, Ljubljana 1000, Slovenia.
2
Department of Chemistry and Biochemistry, Universidad CEU San Pablo, Boadilla del Monte, Madrid 28668, Spain, Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gdańsk 80-416, Poland.
3
Department of Biotechnology, National Institute of Chemistry, Ljubljana 1000, Slovenia, Centre of Excellence NMR - Future Innovation for Sustainable Technologies, Ljubljana 1000, Slovenia.
4
Infection and Cystic Fibrosis Unit, Istituto di Ricovero e Cura a Carattere Scientifico-San Raffaele Scientific Institute, Milan 20132, Italy.
5
From the Departments of Chemical Sciences and.
6
Biology, University of Naples Federico II, Naples 80126, Italy.
7
Department of Microbiology and Immunology, University of Western Ontario, London N6A 5C1, Canada.
8
Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, University of Newcastle, Newcastle NE1 7RU, United Kingdom, and.
9
Department of Microbiology and Immunology, University of Western Ontario, London N6A 5C1, Canada, Centre for Infection and Immunity, Queen's University Belfast, Belfast BT9 7AE, United Kingdom.
10
Department of Chemistry and Biochemistry, Universidad CEU San Pablo, Boadilla del Monte, Madrid 28668, Spain, smsantamaria@cib.csic.es.
11
From the Departments of Chemical Sciences and molinaro@unina.it.

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.

KEYWORDS:

Burkholderia; Gram-negative bacteria; TLR4/MD-2; cystic fibrosis; innate immunity; lipopolysaccharide (LPS); molecular modeling

PMID:
26160169
PMCID:
PMC4571861
DOI:
10.1074/jbc.M115.649087
[Indexed for MEDLINE]
Free PMC Article

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