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Pseudomonas aeruginosa lipid A diversity and its recognition by Toll-like receptor 4

Department of Medicine, University of Washington, Seattle, Washington, USA, rkernst{at}u.washington.edu

Adeline M. Hajjar

Department of Immunology, University of Washington, Seattle, Washington, USA

Jeff H. Tsai

Department of Immunology, University of Washington, Seattle, Washington, USA

Samuel M. Moskowitz

Department of Pediatrics, University of Washington, Seattle, Washington, USA

Christopher B. Wilson

Department of Immunology, University of Washington, Seattle, Washington, USA, Department of Pediatrics, University of Washington, Seattle, Washington, USA

Samuel I. Miller

Department of Medicine, University of Washington, Seattle, Washington, USA, Department of Genome Sciences, University of Washington, Seattle, Washington, USA, Department of Microbiology, University of Washington, Seattle, Washington, USA

Lipid A is the pro-inflammatory component of bacterial lipopolysaccharide, the major surface component of Gram-negative bacteria. Gram-negative bacteria alter the structure of lipid A in response to specific environmental conditions including those found upon colonization of a host. The opportunistic pathogen Pseudomonas aeruginosa synthesizes a unique hexa-acylated lipid A containing palmitate and aminoarabinose during adaptation to the cystic fibrosis airway. Different lipid A species are observed in P. aeruginosa isolated from non-cystic fibrosis associated infections. Here we report that P. aeruginosa isolates from the airway of a cystic fibrosis patient with severe pulmonary disease synthesized a novel hepta-acylated lipid A. Cystic fibrosis-specific P. aeruginosa lipid A modifications result in resistance to host antimicrobial peptides and increased recognition by human Toll-like receptor 4 (TLR4). Using P. aeruginosa lipid A with different levels of acylation, we identified a 222 amino acid region in the extracellular portion of human TLR4 that is required for the differential recognition of cystic fibrosis-specific lipid A. P. aeruginosa adaptation to the human airway may, therefore, play a fundamental role in the progressive lung damage associated with cystic fibrosis.

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