thumb|250px|class=skin-invert|Chemical structure of lipid A as found in E. coli

Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane. 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.

Chemical composition

Lipid A consists of two glucosamine (aminosugar) units, in a β(1→6) linkage, with attached acyl chains ("fatty acids"), and normally containing one phosphate group on each carbohydrate.]]

[[image:LipidASynth2.gif|center|thumb|700px|Synthesis of Lipid IV<sub>a</sub>

On the other hand, modified versions of lipid A can be used as components of vaccines (adjuvants) to improve their effect. Monophosphorylated lipid A (MPL) is an FDA approved adjuvant that consists of a heterogeneous mixture of lipid A from Salmonella 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.

The biological activity of LPS depends on the chemical structure of its lipid A. Primarily, TLR4 is required for activation of innate immunity upon recognition of LPS of Gram-negative bacteria. The ability of TLR4/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 the TLR4/MD-2 complex, dampening the host immune response and increasing the risk of bacterial dissemination. On the other hand, such lipid A would not be able to induce septic 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 the immune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.

Mechanism of activating cells

Lipid A (and LPS) has been demonstrated to activate cells via Toll-like receptor 4 (TLR4), MD-2 and CD14 on the cell surface. Consequently, lipid A analogs like eritoran can act as TLR4 antagonists. They are being developed as drugs for the treatment of excessive inflammatory responses to infections with gram-negative bacteria.

See also

  • Lipid A deacylase (PagL)

References

  • The Lipid Library - Summary of Lipid A and bacterial polysaccharides