Role of lipid A palmitoylation in bacterial pathogenesis

Abstract

The presence of palmitate in a minor fraction of lipid A has been known since the chemical structure of lipid A was first elucidated, but the functional importance in bacterial pathogenesis of regulated lipid A palmitoylation has become clear only recently. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP. The isolation of pagP mutants from pathogenic Gram-negative bacteria has revealed that palmitoylated lipid A can both protect the bacterium from certain host immune defenses and attenuate the ability of lipid A to activate those same defenses through the TLR4 signal transduction pathway. The mechanisms by which bacteria regulate the incorporation of palmitate into lipid A strikingly reflect the corresponding organism's pathogenic lifestyle. Variations on these themes can be illustrated with the known pagP homologs from Gram-negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is now lending itself both as a target for the development of anti-infective agents, and as a tool for the synthesis of lipid A-based vaccine adjuvants and endotoxin antagonists.