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

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.