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Review
. 2007 Sep;297(5):277-95.
doi: 10.1016/j.ijmm.2007.03.012. Epub 2007 Apr 27.

Pseudomonas aeruginosa lipopolysaccharide: a major virulence factor, initiator of inflammation and target for effective immunity

Gerald B Pier  1
Affiliations
Review

Pseudomonas aeruginosa lipopolysaccharide: a major virulence factor, initiator of inflammation and target for effective immunity

Gerald B Pier. Int J Med Microbiol. 2007 Sep.

Erratum in

  • Int J Med Microbiol. 2007 Nov;297(7-8):641

Abstract

Pseudomonas aeruginosa is one of the most important bacterial pathogens encountered by immunocompromised hosts and patients with cystic fibrosis (CF), and the lipopolysaccharide (LPS) elaborated by this organism is a key factor in virulence as well as both innate and acquired host responses to infection. The molecule has a fair degree of heterogeneity in its lipid A and O-antigen structure, and elaborates two different outer-core glycoforms, of which only one is ligated to the O-antigen. A close relatedness between the chemical structures and genes encoding biosynthetic enzymes has been established, with 11 major O-antigen groups identified. The lipid A can be variably penta-, hexa- or hepta-acylated, and these isoforms have differing potencies when activating host innate immunity via binding to Toll-like receptor 4 (TLR4). The O-antigen is a major target for protective immunity as evidenced by numerous animal studies, but attempts, to date, to produce a human vaccine targeting these epitopes have not been successful. Newer strategies employing live attenuated P. aeruginosa, or heterologous attenuated bacteria expressing P. aeruginosa O-antigens are potential means to solve some of the existing problems related to making a P. aeruginosa LPS-specific vaccine. Overall, there is now a large amount of information available about the genes and enzymes needed to produce the P. aeruginosa LPS, detailed chemical structures have been determined for the major O-antigens, and significant biologic and immunologic studies have been conducted to define the role of this molecule in virulence and immunity to P. aeruginosa infection.

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Figures

Fig. 1
Fig. 1
Structures of variant P. aeruginosa lipid A found to be predominantly expressed in isolates from CF patients (CF lipid A), bronchiectasis patients (BR lipid A) or from a laboratory adapted (LA lipid A) strain, PAK. Reprinted with permission from Nature Publishing Group from (Hajjar et al., 2002).
Fig. 2
Fig. 2
General structure of the two glycoforms of the P. aeruginosa LPS core. The inner core comprises the 2 Kdo and 2 heptose (Hep) residues; the outer core the remainder of the molecule. For more detail see (Bystrova et al., 2006) where a similar version of the figure originally appeared. Rha-rhamnose; Glc=glucose; GalN=N-acetyl galactosamine; Ala=alanine; Hep=heptose; Kdo=2-keto-oc2lusonic acid; P=mono- or di-phosphate; EtNP= ethanolamine phosphate.
Fig. 3
Fig. 3
Schematic depiction of the different O-antigen biosynthetic gene clusters of P. aeruginosa. Genes are identified by arrows drawn to scale and protein families shown as single-letter designations. Open reading frames with possible membrane-spanning domains are designated with a W. When known, specific genes are shown above the clusters. The C-terminal coding region of wbpM, shown as an open arrow, is presumed to extend rightward of the cloned region, as shown. Shown along the right-hand edge is the G+C content for each of the biosynthetic loci. Reprinted with permission of the American Society for Microbiology from (Raymond et al., 2002).
Fig. 4
Fig. 4
Activation of innate immune signaling pathways by binding of LPS to TLR4-MD-2, facilitated by CD14. TLR4, along with other TLRs such as TLR2, and cytokine receptors such as the interleukin-1 receptor type 1 (IL-1Rc type 1) utilize a variety of adaptor molecules to transmit the information of ligand binding to the nucleus in order to induce cytokine and other responses. MyD88 (myeloid differentiation factor 88); TIRAP: (TIR domain-containing adaptor protein); TRAF-6 (tumor necrosis factor receptor–associated factor 6); TAK-1 (transforming growth factor β-activating kinase 1); TAB1 TAB2, and TAB3 (TAK1-binding protein 1, 2 or 3); IKK-α, -β, and -γ. IKK-γ (Inducible kinase, IKK-γ is also called NEMO [nuclear factor κB (NF-κB) essential modulator]); IκB (inhibitor of NF-κB); PP-IκB (phosphorylated IκB); JNK (c-Jun N-terminal kinase). Modified from (Pier, 2004) and reprinted with permission from McGraw-Hill publishers.
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