bacterial pathogens, virulence genes often encode secreted toxic proteins (toxins) that interact with host cell structural or signaling proteins to elicit a response that is beneficial to the pathogen. Several of these bacterial toxins are among the most potent of known human poisons. Bacterial toxins are often composed of two protein components—an A subunit with enzymatic activity, and a B subunit that binds to specific receptors on the host cell surface and directs the trafficking of the A subunit to the cytosol by various routes (Figure 23–6). The Vibrio cholerae phage, for example, encodes the two subunits of cholera toxin (Movie 23.2). The A subunit catalyzes the transfer of an ADP-ribose moiety from NAD+ to the trimeric G protein Gs (see Figure 15–23), which activates adenylyl cyclase to make cyclic AMP (see Figure 15–25). ADP-ribosylation prevents inactivation of the G protein and results in the overaccumulation of intracellular cyclic AMP and the release of ions and water into the intestinal lumen, leading to the watery diarrhea associated with cholera. The infection then spreads to new hosts via released bacteria, which can contaminate food and water.
Some pathogenic bacteria secrete multiple toxins, each of which targets a different signaling pathway in host cells. Anthrax, for example, is an acute infectious disease of sheep, cattle, and occasionally humans. It is caused by contact with spores of the Gram-positive bacterium Bacillus anthracis. Dormant spores can survive in soil for long periods. If inhaled, ingested, or rubbed into breaks in the skin, spores can germinate and the bacteria replicate. The bacteria secrete two toxins with identical B subunits but different A subunits. The B subunits bind to a host cell-surface receptor protein to transfer the two different A subunits into
Figure 23–6 Bacterial toxin entry into host cells. Bacterial toxins are often composed of A and B protein subunits. The B (binding) subunit of the toxin interacts with host-cell toxin receptors, enabling endocytosis and intracellular trafficking of B subunit as well as its associated and enzymatically active A subunit(s). In the case of Bacillus anthracis, the B subunit changes conformation in the low pH environment of the endosome to form a pore through which two different A subunits, lethal factor and edema factor, are transported across the membrane of the endosome in an unfolded conformation. In the cases of Vibrio cholerae toxin and Bordetella pertussis toxin, the B and A subunits are transported to the Golgi apparatus and then to the endoplasmic reticulum (ER), where the A subunits are then translocated into the cytosol in an unfolded conformation through a proteintranslocation channel.
host cells (see Figure 23–6). The A subunits are called lethal factor and edema factor. The A subunit of edema toxin is an adenylyl cyclase that catalyzes the production of cyclic AMP (see Figure 15–25), leading to an ion imbalance that can cause an accumulation of extracellular fluid (edema) in the skin or lung. The A subunit of lethal toxin is a protease that cleaves several activated members of the mitogen-activated protein kinase kinase (MAP kinase kinase) family (see Figure 15–49), disrupting intracellular signaling and leading to immune cell dysfunction and cell death. Injection of lethal toxin into the bloodstream of an animal causes shock (a large fall in blood pressure) and death.