Cord factor

Cord factor, or trehalose dimycolate, is a glycolipid molecule found in the cell wall of Mycobacterium tuberculosis and similar species. It is the primary lipid found on the exterior of M. tuberculosis cells. Cord factor influences the arrangement of M. tuberculosis cells into long and slender formations, giving its name. Cord factor is virulent towards mammalian cells and critical for survival of M. tuberculosis in hosts, but not outside of hosts. Cord factor has been observed to influence immune responses, induce the formation of granulomas, and inhibit tumor growth.

A cord factor molecule is composed of a trehalose sugar, a disaccharide, that is esterified to two mycolic acid residues. One of the two mycolic acid residues is attached to the sixth carbon of one monosaccharide, while the other mycolic acid residue is attached to the sixth carbon of the other monosaccharide. Therefore, cord factor is also named trehalose-6,6'-dimycolate. The carbon chain of the mycolic acid residues vary in length depending on the species of bacteria it is found in, but the general range is 20 to 80 carbon atoms. Cord factor's amphiphilic nature leads to varying structures when many cord factor molecules are in close proximity. On a hydrophobic surface, they spontaneously form a crystalline monolayer. This crystalline monolayer is extremely durable and firm; it is stronger than any other amphiphile found in biology. This monolayer also forms in oil-water, plastic-water, and air-water surfaces. In an aqueous environment free of hydrophobic surfaces, cord factor forms a micelle. Furthermore, cord factor interlocks with lipoarabinomannan (LAM), which is found on the surface of M. tuberculosis cells as well, to form an asymmetrical bilayer.

A large quantity of cord factor is found in virulent M. tuberculosis, but not in avirulent M. tuberculosis. Furthermore, M. tuberculosis loses its virulence if its ability to produce cord factor molecules is compromised. Consequently, when all lipids are removed from the exterior of M. tuberculosis cells, the survival of the bacteria is reduced within a host. When cord factor is added back to those cells, M. tuberculosis survives at a rate similar to that of its original state. Cord factor increases the virulence of tuberculosis in mice, but it has minimal effect on other infections.

The function of cord factor is highly dependent on what environment it is located, and therefore its conformation. This is evident as cord factor is harmful when injected with an oil solution, but not when it is with a saline solution, even in very large amounts. Cord factor protects M. tuberculosis from the defenses of the host. Specifically, cord factor on the surface of M. tuberculosis cells prevents fusion between phagosomal vesicles containing the M. tuberculosis cells and the lysosomes that would destroy them. The individual components of cord factor, the trehalose sugars and mycolic acid residues, are not able to demonstrate this activity; the cord factor molecules must be fully intact. Esterase activity that targets cord factor results in the lysis of M. tuberculosis cells. However, the M. tuberculosis cells must still be alive to prevent this fusion; heat-killed cells with cord factor are unable to prevent being digested. This suggests an additional molecule from M. tuberculosis is required. Regardless, cord factor's ability to prevent fusion is related to an increased hydration force or through steric hindrance. Cord factor remains on the surface of M. tuberculosis cells until it associates with a lipid droplet, where it forms a monolayer. Then, as cord factor is in a monolayer configuration, it has a different function; it becomes fatal or harmful to the host organism. Macrophages can die when in contact with monolayers of cord factor, but not when cord factor is in other configurations. As the monolayer surface area of cord factor increases, so does its toxicity. The length of the carbon chain on cord factor has also shown to affect toxicity; a longer chain shows higher toxicity. Furthermore, fibrinogen has shown to adsorb to monolayers of cord factor and act as a cofactor for its biological effects.

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