The O-antigen is attached to the core polysaccharide and is the outermost part of the molecule. Although not toxic, it is the main immunogenic portion of endotoxins and consequently, it is a recognition target for antibodies and a major antigenic determinant. It is a repetitive glycan polymer made up of 3 to 5 sugars. It is the most diverse component of LPS: composition and length vary among species and even strains of bacteria.
Function of endotoxins
Endotoxins are the main component of the outer membrane of Gram-negative bacteria and of vital importance to their survival. Endotoxins contribute to the structural integrity of bacteria and act as a protective amphipathic barrier, shielding bacteria from chemical attacks. Endotoxins establish a barrier that is permeable only to hydrophilic molecules with low molecular weight, making Gram-negative bacteria resistant to many antimicrobial compounds.3
The reduced permeability to large hydrophilic molecules mainly results from the hydrophobic nature of Lipid A. The hydrophilic nature of the core oligosaccharide and O-antigen additionally make endotoxins impermeable to hydrophobic compounds.
In hosts, LPS protects bacteria from killing by phagocytes or serum components. Of notice, variations in the endotoxin structure establish different antigenic strains, increasing their chance of circumventing immunological responses that were previously developed against a specific strain of bacteria, allowing resistance to evolve.
As endotoxins are exposed on the surface of bacteria, the innate immune system has evolved to recognise them as a threat and to react accordingly to their presence. Endotoxins are pyrogens, provoking a strong innate immune response. When Gram-negative bacteria are killed by the immune system, fragments of their membrane containing endotoxins are released in the blood stream and may cause fever and diarrhoea. The presence of endotoxins in the blood (endotoxemia) typically leads to hypotension, respiratory failure and reduced oxygen delivery.4 Strong endotoxemia can lead to sepsis and eventually death.
Being the most conserved portion of LPS, the immune system has evolved to respond predominantly to Lipid A. The immune reaction is entirely innate and mediated by Toll-Like Receptor 4 (TLR4) in complex with MD2 (fig.4).5