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Lipopolysaccharide Heterogeneity: Innate Host Responses to Bacterial Modification of Lipid A Structure

¹ Department of Periodontics, University of Washington, Health Sciences Center, Box 357444, Seattle, WA 98195, USA; and
² The United States Army Dental Corps;

View larger version (72K): [in a new window]   Figure 1. General overview of lipopolysaccharide (LPS) on the outer membrane of a Gram-negative bacterium. LPS consists of 3 major components: the highly variable outer O-antigen segment; a more conserved core, which is divided into outer and inner segments; and the bioactive lipid A portion. Variation within the length of the LPS, due to mutational absence of specific structures, not only changes the phenotypic appearance of the bacterium (i.e., smooth [S], semi-rough [SR], or rough [R]), but may also change some bioactive responses by the host to the bacterium itself. (A) Some bacterial species contain an outer capsule that protects the bacterium from host defenses such as complement, lysis, and phagocytosis. (B) Outer lipid bilayer with LPS which is approximately 8 nm in width. (C) Peptidoglycan layer. (D) Inner bilipid membrane. Note: Additional lipoproteins, porin complexes, and additional membrane proteins established within and surrounding the inner and outer membranes have been removed to simplify the diagram (Raetz, 1992; Caroff et al., 2002).

View larger version (15K): [in a new window]   Figure 2. Lipid A chemical structure examples. (A) Representative lipid A structure for E. coli with a mass ion m/z 1798. The mass ion at m/z 1798 accounts for greater than 80% of the lipid A found in E. coli. It consists of a phosphorylated ß(1'-6) D-glucosamine disaccharide substituted with hydroxylated and non-hydroxylated fatty acids. LpxA and LpxD transfer the indicated fatty acids to monomers N-acetyl-glucosamine 1 (GlcN 1) and N-acetyl-glucosamine 2 (GlcN 2). Next, the ß(1'-6)-linked disaccharide is generated by a disaccharide synthase encoded by lpxB. lpxK is the kinase structural gene responsible for phosphorylating the disaccharide. Two Kdo residues are transferred to the lipid A disaccharide by a bifunctional enzyme encoded by waaA/kdtA. Following the GlcN subunits’ condensing to form a disaccharide, and in the presence of Kdo, lpxL and lpxM transfer the indicated secondary fatty acids to lipid A (Caroff et al., 2002; Raetz and Whitfield, 2002). (B) Chemical structure of the synthetic intermediate lipid A product (labeled Lipid IVA, compound 406, or LA-14-PP), containing low bioactivity and antagonistic properties in certain cell lines (Wang et al., 1990; Takada and Kotani, 1992; Raetz and Whitfield, 2002).

View larger version (22K): [in a new window]   Figure 3. Heterogeneity of P. gingivalis lipid A may contribute to innate host response modulation. The basic structure of lipid A for P. gingivalis 381 was described by Ogawa (1993) as a monophosphorylated tri-acylated disaccharide with a negative ion FAB MS-MS mass ion located at m/z 1195, which displayed low endotoxic activity. Later, Kumada et al.(1995) reported additional P. gingivalis lipid A moieties (within a clinical isolate) to include lipid A species containing 4 or 5 fatty acid chains, with a negative ion FAB MS-MS mass ion(s) located at m/z 1435, 1449, 1690, and 1770, respectively. The addition or subtraction of specific lipid A components from the parent moiety (m/z 1690 in this example) can be accomplished naturally through enzymatic function. Membrane-associated enzymes (depicted by arrows) that possess this capability, whose function is environmentally or gene-regulated (Bishop et al., 2000; Trent et al., 2001; Kawasaki et al., 2004), might help explain natural heterogeneity within lipid A of P. gingivalis. Characterization of predicted innate host response effects toward these structural differences is currently under way (Ogawa and Uchida, 1996; Ogawa et al., 2002; Darveau et al., 2004).

View larger version (51K): [in a new window]   Figure 4. Bacterial modification of lipid A leads to changes in innate host response. Panel (A) LPS consist of three distinct regions formerly thought to contain a highly variable outer O-chain, a ‘semi-conserved’ middle core segment, as well as a highly conserved lipid A anchor. However, as more examples of natural heterogeneity become apparent, the once ‘highly conserved’ lipid A segment is being recognized as a site in which bacterial modification can result in multiple forms or moieties of lipid A structure, each with a potentially distinct effect on the innate host response. Examples of natural heterogeneity within lipid A and innate host effects are represented in panel (B). Here, heterogeneity can arise from: temperature changes from flea vector to host, as seen in Yersinia pestis (Kawahara et al., 2002; Rebeil et al., 2004); by PhoP/PhoQ-controlled mechanisms in S. typhimurium and P. aeruginosa (Guo et al., 1997; Ernst et al., 1999; Bishop et al., 2000; Trent et al., 2001); as well as specific environmental conditions and membrane-associated enzymes currently being examined in P. gingivalis. Specific host responses toward these lipid A modifications are described in the text.