Lipopolysaccharide (LPS,
endotoxin) is a structural component of the gram-negative outer membrane. The
lipid A moiety of LPS binds to the
LPS receptor complex expressed by leukocytes, endothelial cells, and parenchymal cells and is the primary component of gram-negative bacteria that is recognized by the immune system. Activation of the
LPS receptor complex by native
lipid A induces robust
cytokine production, leukocyte activation, and
inflammation, which is beneficial for clearing
bacterial infections at the local level but can cause severe systemic
inflammation and
shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to
shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with
lipid A has also been shown to augment the host response to
infection and to serve as a potent
vaccine adjuvant. However, the adverse effects associated with the pronounced inflammatory response limit the use of native
lipid A as a clinical
immunomodulator. More recently, analogs of
lipid A have been developed that possess attenuated proinflammatory activity but retain attractive immunomodulatory properties. The
lipid A analog
monophosphoryl lipid A exhibits approximately 1/1,000th of the toxicity of native
lipid A but retains potent
immunoadjuvant activity. As such,
monophosphoryl lipid A is currently used as an adjuvant in several human
vaccine preparations. Because of the potency of
lipid A analogs as
immunoadjuvants, numerous laboratories are actively working to identify and develop new
lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics,
lipid A analogs represent an attractive family of
immunomodulators.