Endotoxin: lipopolysaccharide and septic shock

Endotoxin is a toxic part of a bacterium's own structure, and the bacterium does not secrete it. It is the lipopolysaccharide (LPS, a large molecule made of fat and sugar) found in the outer membrane, the extra outer layer of the cell wall, of Gram-negative bacteria (bacteria with two membranes and a thin wall between them). The toxic part of LPS is lipid A, the portion that anchors it in the membrane.

Endotoxin is released mainly when the bacterium dies or divides. The innate immune system (the fast, non-specific first line of defence) detects lipid A through Toll-like receptor 4, a sensor on immune cells. This switches on the release of cytokines (chemical messengers of inflammation), which cause fever. At a small, contained focus of infection this response helps to clear the bacteria.

In severe bacteraemia (bacteria circulating in the blood), the cytokine release becomes excessive and body-wide. Blood vessels dilate and leak, clots form in the smallest vessels, and tissues receive too little blood. That is how endotoxin leads to hypotension (low blood pressure) and septic shock, with organs receiving too little oxygen.

Endotoxin also leaves little lasting immune memory, the ability of the adaptive (specific, learned) immune system to respond faster and more strongly to a second exposure. Lipopolysaccharide is a thymus-independent antigen, one that can stimulate B cells to make antibodies without help from T cells, so it gives only brief adaptive memory. Protein exotoxins are the contrast: living bacteria secrete them, they damage specific target cells, and antibodies can neutralise them, which is why toxoid vaccines (made from inactivated exotoxins) work.