Lipid A is alipid component of anendotoxin held responsible for thetoxicity ofgram-negative bacteria. It is the innermost of the three regions of thelipopolysaccharide (LPS), also calledendotoxin molecule, and itshydrophobic nature allows it to anchor the LPS to theouter membrane.[2] While its toxic effects can be damaging, the sensing of lipid A by the immune system may also be critical for the onset of immune responses to gram-negative infection, and for the subsequent successful fight against the infection.[3]
Lipid A consists of twoglucosamine (aminosugar) units, in a β(1→6) linkage, with attachedacyl chains ("fatty acids"), and normally containing onephosphate group on eachcarbohydrate.[1]
The optimal immune activating lipid A structure is believed to contain 6 acyl chains. Four acyl chains attached directly to the glucosamine sugars arebeta hydroxy acyl chains usually between 10 and 16 carbons in length. Two additional acyl chains are often attached to the betahydroxy group.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.[1]
The biosynthetic pathway for Lipid A inE. coli has been determined by the work ofChristian R. H. Raetz in the past >32 years.[2] Lipid A structure and effects on eukaryotic cells have been determined and examined, among others, by the groups of Otto Westphal, Chris Galanos, Ernst T. Rietschel and Hajime Takahashi starting already in the 1960s (Gmeiner, Luederitz, Westphal. Eur J Biochem 1969)(Kamio&Takahashi J Biochem 1971)(Luederitz, Galanos et al., J Infect Dis 1973).
The enzymes involved in Lipid A synthesis are conserved amongPseudomonas aeruginosa,Escherichia coli,Bordetella bronchiseptica, andSalmonella.[4]
Many of the immune activating abilities of LPS can be attributed to the lipid A unit. It is a very potent stimulant of theimmune system, activating cells (for example,monocytes ormacrophages) atpicogram per milliliter quantities.
When present in the body at high concentrations during a gram-negative bacterial infection, it may cause shock and death by an "out of control" excessive immune reaction.
Lipid A with a reduced number of acyl chains (for example; four) can serve as an inhibitor of immune activation induced by Gram-negative bacteria, and synthetic versions of these inhibitors (Eritoran) were in clinical trials for the prevention of harmful effects caused bygram-negative bacterial infections. However, trials were recently discontinued due to lack of efficacy seen in patients with severe sepsis.[5]
On the other hand, modified versions of lipid A can be used as components ofvaccines (adjuvants) to improve their effect.[6] Monophosphorylated lipid A (MPL) is an FDA approved adjuvant that consists of a heterogeneous mixture of lipid A fromSalmonella minnesota R595. The major lipid A species present in MPL lacks one of the two phosphate groups and five acyl chains. Other work has shown that the removal of one or two acyl chains from native lipid A can significantly reduce activation of inflammatory responses.[7]
The biological activity ofLPS depends on the chemical structure of its lipid A. Primarily,TLR4 is required for activation ofinnate immunity upon recognition of LPS ofGram-negative bacteria. The ability ofTLR4/MD-2 system to respond to a distinct lipid A species are clinically important.Pathogenic bacteria may employ LPS with low biological activity of its lipid A to evade proper recognition by theTLR4/MD-2 complex, dampening the hostimmune response and increasing the risk of bacterial dissemination. On the other hand, such lipid A would not be able to induceseptic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar lipid A species may affect the activation of theimmune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.[8]
Lipid A (and LPS) has been demonstrated to activate cells via Toll-like receptor 4 (TLR4),MD-2 andCD14 on the cell surface.[9][10][11] Consequently, lipid Aanalogs likeeritoran can act as TLR4antagonists. They are being developed as drugs for the treatment of excessive inflammatory responses to infections with gram-negative bacteria.[12]
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