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Bacterial Toxins

The views expressed are those of the author and are not necessarily those of Scientific American.


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This post was chosen as an Editor's Selection for ResearchBlogging.orgKey to the development of disease in many bacterial infections is expression of a bacterial toxin. Toxins come in many shapes and forms but all have a pretty similar goal, to directly induce damage to the cells of the host.

Skull and crossbones

Universally recognised symbol for toxins and pirates. Credit - Wikimedia

 

Toxins seem to conflict with the idea that pathogens are simply commensal bacteria that have lost the ability to tone down an attack once established in a host. What good is the host as a food source if you kill the host with your suite of toxins? But toxins are often integral to the normal lifecycle of the bacterium.

Pigeon-holing toxins into groups is a bit of a task but some generalised labels based of toxin function help to define what you can expect from the large and diverse types of bacterial toxins out there.

The first major group of toxins are the pore forming toxins or membrane damaging toxins. These toxins associate with the membranes of specific host cell types then assemble into multi-subunit hole punchers that insert holes into the hosts membrane. Obviously this is less than ideal for the host cell as its insides become part of its outsides and the cell dies.

One of the most potent pore forming toxins is called pneumolysin, which can be recovered from Streptococcus pneumoniae. This bacteria actually expresses two toxins but one, autolysin, attacks its own surface causing a kamikaze type effect. Pneumolysin can’t be exported from the bacterial cell so the kamikaze mechanism allows release of pneumolysin following the sacrifice of the bacterial cell. Pneumolysin assembles approximately 40 subunits before punching holes in the membranes of the cells in your lungs causing tissue damage and fluid leakage (resulting in the pneumonia for which its named) and also providing easier access to the blood stream allowing migration of s. pneumoniae into the blood and subsequently other tissues.

Pneumolysin subunit. Credit - Tilley et al.

The second major group of bacterial toxins are defined by their ability to inhibit protein synthesis. The ability to make proteins is fundamental to healthy cells and a host cell that doesn’t make proteins is a very soon to be a dead cell. The inhibition of protein synthesis can occur in many ways but two of the deadliest toxins on Earth, Shiga toxin and diptheria toxin, use the two most common methods.

Shiga toxin type 2 (Stx2) from from Escherichia coli O157-H7 PDB 1r4p

Shiga toxin from E. coli O157:H7. Credit - Fraser et al.

Shiga toxin is part of a group of structurally related toxins called the AB5 toxins. AB5 toxins, as the name suggests, are comprised of two different subunits, A and B. The A, or catalytic, subunit it the part of the toxin which has toxin activity whereas the 5 B subunits are involved in binding of the toxin to its receptor. The designation ‘AB5’ is a structural grouping that can further divide functional groups of toxins into smaller, more specific groups.

In any case the Shiga toxin acts by cleaving an adenine residue in ribosomal RNA of host cells. Without functioning ribosomes protein synthesis is impossible and consequently so is the continued living of that cell.

PDB 1xdt EBI

Diptheria toxin. Credit - European Bioinformatics Institute

Diptheria toxin also inhibits protein synthesis but instead catalyses a reaction on elongation factor 2 causing its ADP-ribosylation and inactivation. Elongation factors are involved the formation of the peptide bond between amino acids so again, if you cant stitch you amino acids together you get no proteins and then death of the cell.

The third major group of bacterial toxins are those that activate secondary messenger pathways. Signalling throughout complex organisms is very complicated and it is made even more so as some signals cant actually enter cells to pass on their message. To overcome this host cells have developed elaborate secondary messenger systems that relay the signal inside the cell so its message can be passed on. These signals can drive cell growth, differentiation, death and much more nuanced responses such as boosting blood glucose or releasing adrenaline. If you interfere with these pathways you can make lots of weird stuff happen inappropriately.

Probably the most famous member of this functional family of toxins, and probably the most famous toxin in the world, is produced by Clostridium botulinum, botulinum toxin. Botulinum toxin inhibits muscle contraction by inhibiting the release of a neural hormone, acetylcholine. Simply put, if acetylcholine is released onto a muscle it will contract and this toxin’s ability to inhibit acetylcholine’s release prevents muscle contraction. Botuliunum toxin is considered the most potent neurotoxin on the planet and Wikipedia says that:

“a mere 90–270 nanograms of botulinum toxin could be enough to kill an average 90 kg (200 lb) person, and four kilograms of the toxin, if evenly distributed, would be more than enough to kill the entire human population of the world.”

And you should always trust Wikipedia.

Botox

Injectable neurotoxin for your face. Credit - AJC1

Despite that, it has been converted into a cosmetic product, Botox, which is used to prevent contraction of muscles causing the formation of wrinkles. Botox is actually used for less vain reasons as well but it’s the people who have it injected into their faces to make them inexpressive mannequin people that have made it famous.

The fourth major group of bacterial toxins are those that generate immune responses, the so-called superantigen toxins. These toxins force the development of an enormous immune response that outpaces what is required or what is necessary and instead does more harm than good as the body starts to accidentally kill its own cells. As an example a normal antigen might activate .001% of your bodies T-cells but a superantigen may activate as many as 20% and along with all those activated cells comes the cytokine storm that accompanies it.

Staphylococcus aureus makes a number of superantigen toxins designed to force the immune system to overreact and become damaging including an enterotoxin, an exfoliative toxin and toxic shock toxin. In combination these toxins force the immune system into overdrive resulting in harmful fevers, skin rashes and hypotension.

Bacillus anthracis

Bacillus anthracis. Credit CDC via Wikimedia

The final group of bacterial toxins are the proteases. Proteases are simply enzymes capable of breaking down other proteins and many proteases perform this function happily inside all of your cells helping to breakdown broken proteins or intracellular pathogens. The proteases released as toxins are a little more “full-on”. These proteases are able to break lots of different proteins or alternatively, as is the case with the ‘lethal factor’ from Bacillus anthracis can break certain proteins in very specific ways. B. anthracis, like botulinum toxin, inhibits a secondary messenger pathway but instead works by cleaving a host protein called MAPKK*. This protein is involved in relaying signals and when this vital link in the relay is lost the cell can no longer respond to signals to grow and divide.

The evolution of toxins and their persistence in microbial organisms indicates how important they are for the lifecycle of many pathogenic species. They are used to trick the host, gain entry to deeper tissues or kill the host cells and in all cases the bacterial pathogen becomes weaker when they are mutated out of the organism. It is for this reason that lots of research concerning the management of bacterial disease concentrates controlling the toxin weapons these bacterial pathogens bring to the battlefield.

*The MAPK’s or Mitogen Activated Protein Kinases are the most stupidly named proteins around. A kinase adds a phosphate group to another protein. So if you have a MAP and then you find a enzyme that adds a phosphate group to it you logically call it a MAPK. It turns out that MAPK is only active when it has an extra phosphate group added to it, the enzyme which does this is of course called MAPKK because it is a kinase phosphrylating another kinase. MAPKK is also activated by phosphorylation giving us a MAPKKK. If you draw up the pathway you get:

MAPKKK>MAPKK>MAPK>MAP

Nice naming convention…

References
Fraser, M. (2004). Structure of Shiga Toxin Type 2 (Stx2) from Escherichia coli O157:H7 Journal of Biological Chemistry, 279 (26), 27511-27517 DOI: 10.1074/jbc.M401939200
Tilley, S., Orlova, E., Gilbert, R., Andrew, P., & Saibil, H. (2005). Structural Basis of Pore Formation by the Bacterial Toxin Pneumolysin Cell, 121 (2), 247-256 DOI: 10.1016/j.cell.2005.02.033
Louie GV, Yang W, Bowman ME, & Choe S (1997). Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor. Molecular cell, 1 (1), 67-78 PMID: 9659904
Middlebrook JL, & Dorland RB (1984). Bacterial toxins: cellular mechanisms of action. Microbiological reviews, 48 (3), 199-221 PMID: 6436655

James Byrne About the Author: Dr James Byrne has a PhD in Microbiology and works as a science communicator at the Royal Institution of Australia (RiAus), Australia's unique national science hub, which showcases the importance of science in everyday life. Follow on Twitter @JB_blogs.

The views expressed are those of the author and are not necessarily those of Scientific American.






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