Lipid A heterogeneity and its role in the host interactions with pathogenic and commensal bacteria

Abstract

Lipopolysaccharide (LPS) is for most but not all Gram-negative bacteria an essential component of the outer leaflet of the outer membrane. LPS contributes to the integrity of the outer membrane, which acts as an effective permeability barrier to antimicrobial agents and protects against complement-mediated lysis. In commensal and pathogenic bacteria LPS interacts with pattern recognition receptors (e.g LBP, CD14, TLRs) of the innate immune system and thereby plays an important role in determining the immune response of the host. LPS molecules consist of a membrane-anchoring lipid A moiety and the surface-exposed core oligosaccharide and O-antigen polysaccharide. While the basic lipid A structure is conserved among different bacterial species, there is still a huge variation in its details, such as the number, position and chain length of the fatty acids and the decoration of the glucosamine disaccharide with phosphate, phosphoethanolamine or amino sugars. New evidence has emerged over the last few decades on how this lipid A heterogeneity confers distinct benefits to some bacteria because it allows them to modulate host responses in response to changing host environmental factors. Here we give an overview of what is known about the functional consequences of this lipid A structural heterogeneity. In addition, we also summarize new approaches for lipid A extraction, purification and analysis which have enabled analysis of its heterogeneity.

Keywords: bacteria; barrier function; heterogeneity; immune response; lipid A; outer membrane.

Figure 1.

(A)The basic structure of lipid A consists of two glucosamine units, in an β (1→6) linkage, with attached acyl chains and normally containing one phosphate group on each glucosamine. The E. coli lipid A structure contains 6 acyl chains. Primary acyl chains are directly attached to the sugar moieties and usually between 10 and 16 carbons in length, secondary acyl chains are esterified with the beta-hydroxyl groups of primary acyl chains. E. coli lipid A, as an example, typically has four C14 hydroxy acyl chains attached to the sugars and one C14 and one C12 attached to the beta-hydroxy groups. Lipid A is considered the most conserved domain of Gram-negative bacterial LPS but it still shows a great degree of diversity among bacterial species. Differences are found in the number and modifications of the phosphate residues, the number and length of the acyl chains and, though less common, the chemistry of the disaccharide backbone. In E.coli, altering the phosphates, number and position of acyl chains of lipid A individually or in combination can give a wide range of TLR4/MD-2 responses and cytokine production. Modification of lipid A can also provide resistance against antimicrobial peptides by charge repulsion or decreasing of the fluidity of the outer membrane, as well as alter the activation potential of the inflammasome. The presence and length of the secondary acyl chains (R1, R2, and R3) varies between bacteria and is linked to the ability of the lipid A species to induce innate immune function. (B) Some examples showing the variation in lipid A structures from different bacteria. For N. meningitidis, both wildtype and lpxL1 mutant structures are shown; for S.typhimurium, hexa- and hepta-acylated forms are shown.