Evasion of Immune System Detection
Diphtheria toxin is especially destructive because the toxic A fragment is very stable. It is resistant to denaturation by high temperatures and acidic conditions (Middlebrook and Dorland, 1984). In fact, a low pH is actually required during endocytosis of the toxin for the conformational change that allows for fragment A to enter the cytosol (Pappenheimer, Jr., 1993). Active fragment A, the toxic part of the toxin protein, survives in the cytosol significantly longer than Fragment B, deactivated, or purified toxin fragments. Fragment A most likely evades proteolysis because it is bound to a host cell NAD molecule. This binding effectively “hides” the toxin fragment A from the normal mechanisms in the cell that degrade foreign antigen for presentation to the adaptive immunity cells (Middlebrook and Dorland, 1984). T cells of the adaptive immune system can not recognize this pathogen until the bacterial enzymes are degraded and presented on the infected cell surface. If fragment A is able to stay in the cell without being degraded for a relatively long period of time, it can avoid detection by the adaptive immune system for a longer time.
Fragment A is especially potent because it mimics the normal interactions between EF-2 and other molecules involved in translation and therefore has nearly universal recognition of the conserved eukaryotic translation mechanisms. However, diphtheria toxin fragment A does not bind the equivalent elongation factors found in bacteria, and therefore does not prevent translation in the live diphtheria bacteria (Yates et al., 2006).
Fragment A also can avoid immune system detection because most of its antigenic sites recognized by antibodies in the humoral immune response are not exposed in the toxin prior to cleavage. The antigenic sites contained in the toxin molecule must be exposed for a long enough time after cleavage to allow for recognition by antibodies and other effector cells. However, after cleavage fragment A quickly or immediately enters the host cell and from then on would be hidden from detection by the cells of the humoral immune response (Cryz, Welkos and Holmes, 1980).
Cryz, Stanley J., Susan L. Welkos and Randall K. Holmes. "Immunochemical Studies of Diphtherial Toxin and Related Nontoxic Mutant Proteins." Infection and Immunity 30.3 (1980): 835-846.
Middlebrook, John L. and Rebecca B. Dorland. “Bacterial Toxins: Cellular Mechanisms of Action.” Microbiological Reviews 48.3 (1984): 199-221.
Pappenheimer, Jr., A. M. “The Story of a Toxic Protein, 1888-1992.” Protein Science 2 (1993): 292-298.
Yates, Susan P., Rene Jorgensen, Gregers R. Andersen and A. Rod Merrill. "Stealth and Mimicry by Deadly Bacterial Toxins." Trends in Biochemical Sciences 31.2 (2006): 123-133.