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Typhoid toxin

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Typhoid fever is caused by the ingestion of food and water contaminated with the gram-negative bacterium Salmonella enterica serovar Typhi. In 2010 it was estimated that typhoid fever caused approximately 190,000 deaths. Typhi bacteria are deadly because they produce a unique type of AB toxin. Typically AB toxins consist of two subunits: The “A” subunit is the active toxin and the “B” subunit binds to cell surface receptors, triggering endocytosis. Typhoid toxin is known as A2B5 because there are two different A units, CdtB and PltA, and a pentameric B subunit comprised of 5 PltB peptides (see Figure 1).
Figure 1: Typhoid toxin complex shown in a ribbon cartoon structure. The top two protein units are the “A” subunits while the bottom ring of peptides is the “B” subunit.
In epithelial cells, typhoid toxin binds to podocalyxin-like protein 1 (PODXL) receptors. Researchers discovered that by introducing shRNA (short hairpin RNA) the toxin-binding ability of epithelial cells decreased. In addition, they found that when typhoid toxin binds to other cell types the commonalities are carbohydrate moieties on the surface of glycoproteins. After removing these surfaces from the proteins, the binding ability of typhoid toxin was reduced.
Researchers also performed two more experiments on typhoid toxin.
Experiment 1
Since the A subunit contains two different peptides, researchers attempted to determine which subunit or subunits cause typhoid toxicity.
Unlike humans, mice do not have the receptors needed to begin endogenous production of typhoid toxin but nevertheless respond to the toxin itself. Researchers took mice and injected them with concentrated levels of normal typhoid toxin, CdtB only, PltA only, or PltB only. As a control, researchers also observed mice not injected with toxin. To measure the reaction, researchers used weight loss—a symptom of typhoid fever—as a gauge of toxicity levels.
Figure 2: Mice were exposed to concentrated serums of various typhoid toxin subunit proteins and to no toxin. The weight loss was recorded in response to these various exposures. Weight loss is a symptom of typhoid fever and is believed to be an indicator of the presence of typhoid fever. Each dot represents the weight loss of a mouse. The long middle horizontal line in each cluster represents the average weight loss while the smaller lines are the standard deviation for each cluster.
Experiment 2 While investigating the structure of typhoid toxin, researchers discovered a disulfide bond in the junction between PltA and CdtB, the two A subunits. Once this disulfide bond was broken, typhoid toxin with the missing disulfide bond had a similar cell cycle profile to cells not exposed to typhoid toxin (see Figure 3).
Figure 3: The untreated distribution of cells is the usual distribution for healthy cells. The normal wild type (WT) of S. Typhi toxin causes cells to undergo cellular arrest, halting in the G2 phase of the cell cycle. These arrested cells are unable to divide and grow. The CdtBstart superscript, Δ, C, y, s, end superscript 269 version of the S. Typhi toxin has a missing disulfide bond.
Sources: All figures information was adapted from J. Song, X. Gao, J.E. Galán Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin Nature, 499 (2013), pp. 350–354.
Which subunit or subunits of the typhoid toxin is most likely the actual cause of typhoid fever?
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