MicrobiologyBytes

A toxin is a poisonous substance produced by living cells or organisms. Toxins are usually proteins and cause cell death by interacting with biological macromolecules such as enzymes or cellular receptors. Many bacteria produce toxins as virulence factors to allow them to colonize multicellular hosts (Bacterial Toxins: Friends or Foes? 1999 Emerging Infectious Diseases 5, 2). Toxins are of particular interest to biologists for a number of reasons:
- They are often the primary virulence factor for a variety of important pathogenic bacteria.
- Some toxins have played an important part in unraveling signaling pathways in eukaryotic cells.
- Since they are antigenically conserved, harmless inactivated forms of toxins (called toxoids) have been developed as useful vaccines for some diseases (e.g. diptheria).

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Well known examples of bacterial toxins include:

• Botulinum toxin (Clostridium botulinum)
• Tetanus toxin (Clostridium tetani)
• Staphylococcus aureus toxins (Panton-Valentine Leukocidin (PVL) and toxic-shock syndrome toxin (TSST))
• Diphtheria toxin (Corynebacterium diphtheriae)
• Cholera toxin (Vibrio cholerae)
• Shiga toxin (Shigella dysenteriae)
• Escherichia coli toxins, such as those encoded by the enterohemorrhagic strain of E. coli O157:H7.

Many of these toxins are encoded by temperate bacteriophages, viruses which can go through one of two alternative replication cycles on infecting a host bacterium. Lytic growth results in lysis of the host cell and release of new phage particles. Alternatively, in lysogenic growth the phage is integrated into the DNA of the host cell. Most of the genes of these lysogenic phages remain dormant until the virus is induced to enter the lytic cycle. At that point they cause the otherwise innocuous bacteria to release potent toxins which cause disease.

So toxins are important for a number reasons, and in recent years the interest in them has increased further since they are potential weapons for bioterrorism (Medical aspects of toxin weapons. 2005 Toxicology 214: 210-220). This is a major concern since these potent poisons effectively have no antidote. Although the intracellular targets for toxins are diverse, a common and essential step in their virulence is the ability to reach the cytosol, where most toxins exert their effects. Bacterial toxins such as Shiga toxin (Stx) and cholera toxin (Ctx), as well as the plant toxin ricin, have a unique retrograde transport pathway following endocytosis. As members of the AB toxin group, these toxins consist of a receptor-binding B subunit and an enzymatic A subunit. In contrast to anthrax and diphtheria toxins which enter the cytosol directly from endosomes in a pH-dependent manner, these membrane-bound toxins bypass the late endocytic pathway by retrograde transport from early endosomes to the trans-Golgi network (TGN). From the TGN, they traffic through the Golgi apparatus to the endoplasmic reticulum (ER), where they are subsequently translocated into the cytosol. It is believed that this complex retrograde transport mechanism may allow for certain essential steps in toxin activation and transfer, for example cleavage and activation of Stx toxin by host proteases.

In an effort to dissect and inhibit the stepwise trafficking of Stx toxin, a group from the Washington University School of Medicine in St. Louis recently developed a high-throughput luciferase-based assay to screen a library of compounds for their ability to block Stx-mediated inhibition of protein synthesis (Identification and characterization of small molecules that inhibit intracellular toxin transport. Infection and Immunity 2007 75: 4552-4561). From an initial screen of 14,400 molecules, they identified several potential inhibitors, two of which reversibly inhibited the toxin. In contrast to standard genetic approaches, small-molecule inhibitors such as these will provide further insights into the mechanism of toxin transport, and hopefully lead to the identification of compounds with therapeutic potential.

Related:

• Botox is bonkers

This entry was posted on Monday, September 10th, 2007 at 9:39 am and is filed under Bacteria, Biology, Health, Medicine, Microbiology, Podcast, Science, Vaccines. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.